TY - JOUR AB - Oligodendroglia are the responsible cells for myelination in the central nervous system and their involvement in Parkinson's disease (PD) is poorly understood. We performed sn-RNA-seq and image-based spatial transcriptomics of human caudate nucleus and putamen (dorsal striatum) from PD and control brain donors to elucidate the diversity of oligodendroglia and how they are affected by the disease. We profiled a total of ~ 200.000 oligodendroglial nuclei, defining 15 subclasses, from precursor to mature cells, 4 of which are disease-associated. These PD-specific populations are characterized by the overexpression of heat shock proteins, as well as distinct expression signatures related to immune responses, myelination alterations, and disrupted cell signaling pathways. We have also identified impairments in cell communication and oligodendrocyte development, evidenced by changes in neurotransmitter receptors expression and cell adhesion molecules. In addition, we observed significant disruptions in oligodendrocyte development, with aberrant differentiation trajectories and shifts in cell proportions, particularly in the transition from mature oligodendrocytes to disease-associated states. Quantitative immunohistochemical analysis revealed decreased myelin levels in the PD striatum, which correlated with transcriptomic alterations. Furthermore, spatial transcriptomics mapping revealed the distinct localization of disease-associated populations within the striatum, with evidence of impaired myelin integrity. Thus, we uncover oligodendroglia as a critical cell type in PD and a potential new therapeutic target for myelin-based interventions. AU - Barba-Reyes, J.M.* AU - Harder, L.* AU - Salas, S.M. AU - Jaisa-Aad, M.* AU - Muñoz-Castro, C.* AU - Garma, L.D.* AU - Rafati, N.* AU - Nilsson, M.* AU - Hyman, B.T.* AU - Serrano-Pozo, A.* AU - Muñoz-Manchado, A.B.* C1 - 74287 C2 - 57419 TI - Oligodendroglia vulnerability in the human dorsal striatum in Parkinson's disease. JO - Acta Neuropathol. VL - 149 IS - 1 PY - 2025 SN - 0001-6322 ER - TY - JOUR AB - Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype. AU - Corrêa-da-Silva, F.* AU - Carter, J.* AU - Wang, X.Y.* AU - Sun, R.* AU - Pathak, E. AU - Monroy Kuhn, J.M. AU - Schriever, S.C. AU - Maya-Monteiro, C.M.* AU - Jiao, H.* AU - Kalsbeek, M.J.* AU - Moraes-Vieira, P.M.M.* AU - Gille, J.J.P.* AU - Sinnema, M.* AU - Stumpel, C.T.R.M.* AU - Curfs, L.M.G.* AU - Stenvers, D.J.* AU - Pfluger, P.T. AU - Lutter, D. AU - Pereira, A.M.* AU - Kalsbeek, A.* AU - Fliers, E.* AU - Swaab, D.F.* AU - Wilkinson, L.* AU - Gao, Y.* AU - Yi, C.X.* C1 - 70368 C2 - 55539 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion. JO - Acta Neuropathol. VL - 147 IS - 1 PB - Springer PY - 2024 SN - 0001-6322 ER - TY - JOUR AU - Mori, K.* AU - Arzberger, T.* AU - Grässer, F.A.* AU - Gijselinck, I.* AU - May, S.* AU - Rentzsch, K.* AU - Weng, S.M.* AU - Schludi, M.H.* AU - van der Zee, J.* AU - Cruts, M.* AU - van Broeckhoven, C.* AU - Kremmer, E. AU - Kretzschmar, H.A.* AU - Haass, C.* AU - Edbauer, D.* C1 - 71930 C2 - 56488 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Correction to: Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. JO - Acta Neuropathol. VL - 148 IS - 1 PB - Springer PY - 2024 SN - 0001-6322 ER - TY - JOUR AB - We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe2+) to ferric iron (Fe3+) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI. AU - Ryan, F.* AU - Blex, C.* AU - Ngo, T.D.* AU - Kopp, M.A.* AU - Michalke, B. AU - Venkataramani, V.* AU - Curran, L.* AU - Schwab, J.M.* AU - Ruprecht, K.* AU - Otto, C.* AU - Jhelum, P.* AU - Kroner, A.* AU - David, S.* C1 - 70908 C2 - 55803 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury. JO - Acta Neuropathol. VL - 147 IS - 1 PB - Springer PY - 2024 SN - 0001-6322 ER - TY - JOUR AB - Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders. AU - Matosin, N.* AU - Arloth, J. AU - Czamara, D.* AU - Edmond, K.Z.* AU - Maitra, M.* AU - Fröhlich, A.S.* AU - Martinelli, S.* AU - Kaul, D.* AU - Bartlett, R.* AU - Curry, A.R.* AU - Gassen, N.C.* AU - Hafner, K.* AU - Müller, N.S. AU - Worf, K. AU - Rehawi, G. AU - Nagy, C.* AU - Halldorsdottir, T.* AU - Cruceanu, C.* AU - Gagliardi, M.* AU - Gerstner, N. AU - Ködel, M.* AU - Murek, V.* AU - Ziller, M.J.* AU - Scarr, E.* AU - Tao, R.* AU - Jaffe, A.E.* AU - Arzberger, T.* AU - Falkai, P.* AU - Kleinmann, J.E.* AU - Weinberger, D.R.* AU - Mechawar, N.* AU - Schmitt, A.* AU - Dean, B.* AU - Turecki, G.* AU - Hyde, T.M.* AU - Binder, E.B.* C1 - 67403 C2 - 54166 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 439-459 TI - Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex. JO - Acta Neuropathol. VL - 145 IS - 4 PB - Springer PY - 2023 SN - 0001-6322 ER - TY - JOUR AB - Expansion of a (G(4)C(2))(n)repeat inC9orf72causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To directly compare these in vivo, we created congenic poly-GA and poly-PR mice. 40% of poly-PR mice were affected with ataxia and seizures, requiring euthanasia by 6 weeks of age. The remaining poly-PR mice were asymptomatic at 14 months of age, likely due to an 80% reduction of the transgene mRNA in this subgroup. In contrast, all poly-GA mice showed selective neuron loss, inflammation, as well as muscle denervation and wasting requiring euthanasia before 7 weeks of age. In-depth analysis of peripheral organs and blood samples suggests that peripheral organ failure does not drive these phenotypes. Although transgene mRNA levels were similar between poly-GA and affected poly-PR mice, poly-GA aggregated far more abundantly than poly-PR in the CNS and was also found in skeletal muscle. In addition, TDP-43 and other disease-linked RNA-binding proteins co-aggregated in rare nuclear inclusions in the hippocampus and frontal cortex only in poly-GA mice. Transcriptome analysis revealed activation of an interferon-responsive pro-inflammatory microglial signature in end-stage poly-GA but not poly-PR mice. This signature was also found in all ALS patients and enriched inC9orf72cases. In summary, our rigorous comparison of poly-GA and poly-PR toxicity in vivo indicates that poly-GA, but not poly-PR at the same mRNA expression level, promotes interferon responses inC9orf72disease and contributes to TDP-43 abnormalities and neuron loss selectively in disease-relevant regions. AU - LaClair, K.D.* AU - Zhou, Q.* AU - Michaelsen, M.* AU - Wefers, B.* AU - Brill, M.S.* AU - Janjic, A.* AU - Rathkolb, B. AU - Farny, D.* AU - Cygan, M.* AU - Hrabě de Angelis, M. AU - Wurst, W.* AU - Neumann, M.* AU - Enard, W.* AU - Misgeld, T.* AU - Arzberger, T.* AU - Edbauer, D.* C1 - 59426 C2 - 48800 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 121–142 TI - Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. JO - Acta Neuropathol. VL - 140 PB - Springer PY - 2020 SN - 0001-6322 ER - TY - JOUR AB - Extracellular deposition of amyloid beta-protein (A beta) in amyloid plaques and intracellular accumulation of abnormally phosphorylated tau-protein (p-tau) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical and clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between A beta and tau pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice overexpressing human APP with the Swedish mutation (670/671 KM -> NL) (APP23), human wild-type APP (APP51/16), or a proenkephalin signal peptide linked to human A beta(42) (APP48) with tau-transgenic mice overexpressing human mutant 4-repeat tau-protein with the P301S mutation (TAU58). In 6-month-old APP23xTAU58 and APP51/16xTAU58 mice, soluble A beta was associated with the aggravation of p-tau pathology propagation into the CA1/subiculum region, whereas 6-month-old TAU58 and APP48xTAU58 mice neither exhibited significant amounts of p-tau pathology in the CA1/subiculum region nor displayed significant levels of soluble A beta in the forebrain. In APP23xTAU58 and APP51/16xTAU58 mice showing an acceleration of p-tau propagation, A beta and p-tau were co-immunoprecipitated with cellular prion protein (PrP). A similar interaction between PrP, p-tau and A beta was observed in human AD brains. This association was particularly noticed in 60% of the symptomatic AD cases in our sample, suggesting that PrP may play a role in the progression of AD pathology. An in vitro pull-down assay confirmed that PrP is capable of interacting with A beta and p-tau. Using a proximity ligation assay, we could demonstrate proximity (less than 30-40 nm distance) between PrP and A beta and between PrP and p-tau in APP23xTAU58 mouse brain as well as in human AD brain. Proximity between PrP and p-tau was also seen in APP51/16xTAU58, APP48xTAU58, and TAU58 mice. Based on these findings, it is tempting to speculate that PrP is a critical player in the interplay between A beta and p-tau propagation at least in a large group of AD cases. Preexisting p-tau pathology interacting with PrP, thereby, appears to be a prerequisite for A beta to function as a p-tau pathology accelerator via PrP. AU - Gomes, L.A.* AU - Hipp, S.A.* AU - Rijal Upadhaya, A.* AU - Balakrishnan, K.* AU - Ospitalieri, S.* AU - Koper, M.J.* AU - Largo-Barrientos, P.* AU - Uytterhoeven, V.* AU - Reichwald, J.* AU - Rabe, S.* AU - Vandenberghe, R.* AU - von Arnim, C.A.F.* AU - Tousseyn, T.* AU - Feederle, R. AU - Giudici, C.* AU - Willem, M.* AU - Staufenbiel, M.* AU - Thal, D.R.* C1 - 56758 C2 - 47380 CY - 233 Spring St, New York, Ny 10013 Usa SP - 913-941 TI - A beta-induced acceleration of Alzheimer-related tau-pathology spreading and its association with prion protein. JO - Acta Neuropathol. VL - 138 IS - 6 PB - Springer PY - 2019 SN - 0001-6322 ER - TY - JOUR AB - The TCF4 gene encodes for the basic helix-loop-helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medulloblastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somatic TCF4 mutations. Interestingly, many of these mutations have previously been detected as germline mutations in patients with PTHS. We show here that overexpression of wild-type TCF4 in vitro significantly suppresses cell proliferation in MB cells, whereas mutant TCF4 proteins do not to the same extent. Furthermore, RNA sequencing revealed significant upregulation of multiple well-known tumor suppressors upon expression of wild-type TCF4. In vivo, a prenatal knockout of Tcf4 in mice caused a significant increase in apoptosis accompanied by a decreased proliferation and failed migration of cerebellar granule neuron precursor cells (CGNP), which are thought to be the cells of origin for SHH MB. In contrast, postnatal in vitro and in vivo knockouts of Tcf4 with and without an additional constitutive activation of the SHH pathway led to significantly increased proliferation of CGNP or MB cells. Finally, publicly available data from human MB show that relatively low expression levels of TCF4 significantly correlate with a worse clinical outcome. These results not only point to time-specific roles of Tcf4 during cerebellar development but also suggest a functional linkage between TCF4 mutations and the formation of SHH MB, proposing that TCF4 acts as a tumor suppressor during postnatal stages of cerebellar development. AU - Hellwig, M.* AU - Lauffer, M.C.* AU - Bockmayr, M.* AU - Spohn, M.* AU - Merk, D.J.* AU - Harrison, L. AU - Ahlfeld, J.* AU - Kitowski, A.* AU - Neumann, J.E.* AU - Ohli, J.* AU - Holdhof, D.* AU - Niesen, J.* AU - Schoof, M.* AU - Kool, M.* AU - Kraus, C.* AU - Zweier, C.* AU - Holmberg, D.* AU - Schüller, U.* C1 - 55689 C2 - 46472 CY - 233 Spring St, New York, Ny 10013 Usa SP - 657-673 TI - TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma. JO - Acta Neuropathol. VL - 137 IS - 4 PB - Springer PY - 2019 SN - 0001-6322 ER - TY - JOUR AB - Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson's disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alphasyn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT (rho = -0.377, p = 0.048), with olfactory function (rho = -0.668, p = 0.002), and positively correlated with the total LR for RBD to present prodromal PD (rho = 0.531, p = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs. AU - Doppler, K.* AU - Jentschke, H.* AU - Schulmeyer, L.* AU - Vadasz, D.* AU - Janzen, A.* AU - Luster, M.* AU - Hoeffken, H.* AU - Mayer, G.* AU - Brumberg, J.* AU - Booij, J.* AU - Musacchio, T.* AU - Klebe, S.* AU - Sittig-Wiegand, E.* AU - Volkmann, J.* AU - Sommer, C.* AU - Oertel, W.H. C1 - 50862 C2 - 42918 CY - New York SP - 535-545 TI - Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease. JO - Acta Neuropathol. VL - 133 IS - 4 PB - Springer PY - 2017 SN - 0001-6322 ER - TY - JOUR AB - Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients. AU - Schludi, M.H.* AU - Becker, L. AU - Garrett, L. AU - Gendron, T.F.* AU - Zhou, Q.* AU - Schreiber, F.* AU - Popper, B.* AU - Dimou, L.* AU - Strom, T.M. AU - Winkelmann, J. AU - von Thaden, A.* AU - Rentzsch, K.* AU - May, S.* AU - Michaelsen, M.* AU - Schwenk, B.M.* AU - Tan, J. AU - Schoser, B.* AU - Dieterich, M.* AU - Petrucelli, L.* AU - Hölter, S.M. AU - Wurst, W. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Hrabě de Angelis, M. AU - Klopstock, T.* AU - Arzberger, T.* AU - Edbauer, D.* C1 - 50928 C2 - 42815 CY - New York SP - 241–254 TI - Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss. JO - Acta Neuropathol. VL - 134 IS - 2 PB - Springer PY - 2017 SN - 0001-6322 ER - TY - JOUR AB - Deposition of the nuclear DNA/RNA-binding protein Fused in sarcoma (FUS) in cytosolic inclusions is a common hallmark of some cases of frontotemporal lobar degeneration (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). Whether both diseases also share common pathological mechanisms is currently unclear. Based on our previous finding that FUS deposits are hypomethylated in FTLD-FUS but not in ALS-FUS, we have now investigated whether genetic or pharmacological inactivation of Protein arginine methyltransferase 1 (PRMT1) activity results in unmethylated FUS or in alternatively methylated forms of FUS. To do so, we generated FUS-specific monoclonal antibodies that specifically recognize unmethylated arginine (UMA), monomethylated arginine (MMA) or asymmetrically dimethylated arginine (ADMA). Loss of PRMT1 indeed not only results in an increase of UMA FUS and a decrease of ADMA FUS, but also in a significant increase of MMA FUS. Compared to ADMA FUS, UMA and MMA FUS exhibit much higher binding affinities to Transportin-1, the nuclear import receptor of FUS, as measured by pull-down assays and isothermal titration calorimetry. Moreover, we show that MMA FUS occurs exclusively in FTLD-FUS, but not in ALS-FUS. Our findings therefore provide additional evidence that FTLD-FUS and ALS-FUS are caused by distinct disease mechanisms although both share FUS deposits as a common denominator. AU - Suárez-Calvet, M.* AU - Neumann, M.* AU - Arzberger, T.* AU - Abou-Ajram, C.* AU - Funk, E.* AU - Hartmann, H.* AU - Edbauer, D.* AU - Kremmer, E. AU - Göbl, C. AU - Resch, M. AU - Bourgeois, B. AU - Madl, T. AU - Reber, S.* AU - Jutzi, D.* AU - Ruepp, M.D.* AU - Mackenzie, I.R.* AU - Ansorge, O.* AU - Dormann, D.* AU - Haass, C.* C1 - 47935 C2 - 39727 CY - New York SP - 587-604 TI - Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS. JO - Acta Neuropathol. VL - 131 IS - 4 PB - Springer PY - 2016 SN - 0001-6322 ER - TY - JOUR AB - Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. One consequence of the mutation is the formation of different potentially toxic polypeptides composed of dipeptide repeats (DPR) (poly-GA, -GP, -GR, -PA, -PR) generated by repeat-associated non-ATG (RAN) translation. While previous studies focusing on poly-GA pathology have failed to detect any clinico-pathological correlations in C9ORF72 mutation cases, recent data from animal and cell culture models suggested that it may be only specific DPR species that are toxic and only when accumulated in certain intracellular compartments. Therefore, we performed a systematic clinico-pathological correlative analysis with counting of actual numbers of distinct types of inclusion (neuronal cytoplasmic and intranuclear inclusions, dystrophic neurites) for each DPR protein in relevant brain regions (premotor cortex, lower motor neurons) in a cohort of 35 C9ORF72 mutation cases covering the clinical spectrum from those with pure MND, mixed FTD/MND and pure FTD. While each DPR protein pathology had a similar pattern of anatomical distribution, the total amount of inclusions for each DPR protein varied remarkably (poly-GA > GP > GR > PR/PA), indicating that RAN translation seems to be more effective from sense than from antisense transcripts. Importantly, with the exception of moderate associations for the amount of poly-GA-positive dystrophic neurites with degeneration in the frontal cortex and total burden of poly-GA pathology with disease onset, no relationship was identified for any other DPR protein pathology with degeneration or phenotype. Biochemical analysis revealed a close correlation between insoluble DPR protein species and numbers of visible inclusions, while we did not find any evidence for the presence of soluble DPR protein species. Thus, overall our findings strongly argue against a role of DPR protein aggregation as major and exclusive pathomechanism in C9ORF72 pathogenesis. However, this does not exclude that DPR protein formation might be essential in C9ORF72 pathogenesis in interplay with other consequences associated with the C9ORF72 repeat expansion. AU - Mackenzie, I.R.* AU - Frick, P.* AU - Grässer, F.A.* AU - Gendron, T.F.* AU - Petrucelli, L.* AU - Cashman, N.R.* AU - Edbauer, D.* AU - Kremmer, E. AU - Prudlo, J.* AU - Troost, D.* AU - Neumann, M.* C1 - 46822 C2 - 37869 SP - 845-861 TI - Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. JO - Acta Neuropathol. VL - 130 IS - 6 PY - 2015 SN - 0001-6322 ER - TY - JOUR AB - A massive expansion of a GGGGCC repeat upstream of the C9orf72 coding region is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. Despite its intronic localization and lack of a canonical start codon, both strands are translated into aggregating dipeptide repeat (DPR) proteins: poly-GA, poly-GP, poly-GR, poly-PR and poly-PA. To address conflicting findings on the predominant toxicity of the different DPR species in model systems, we compared the expression pattern of the DPR proteins in rat primary neurons and postmortem brain and spinal cord of C9orf72 mutation patients. Only poly-GA overexpression closely mimicked the p62-positive neuronal cytoplasmic inclusions commonly observed for all DPR proteins in patients. In contrast, overexpressed poly-GR and poly-PR formed nucleolar p62-negative inclusions. In patients, most of the less common neuronal intranuclear DPR inclusions were para-nucleolar and p62 positive. Neuronal nucleoli in C9orf72 cases showed normal size and morphology regardless of the presence of poly-GR and poly-PR inclusions arguing against widespread nucleolar stress, reported in cellular models. Colocalization of para-nucleolar DPR inclusions with heterochromatin and a marker of transcriptional repression (H3K9me2) indicates a link to gene transcription. In contrast, we detected numerous intranuclear DPR inclusions not associated with nucleolar structures in ependymal and subependymal cells. In patients, neuronal inclusions of poly-GR, poly-GP and the poly-GA interacting protein Unc119 were less abundant than poly-GA inclusions, but showed similar regional and subcellular distribution. Regardless of neurodegeneration, all inclusions were most abundant in neocortex, hippocampus and thalamus, with few inclusions in brain stem and spinal cord. In the granular cell layer of the cerebellum, poly-GA and Unc119 inclusions were significantly more abundant in cases with FTLD than in cases with MND and FTLD/MND. Poly-PR inclusions were rare throughout the brain but significantly more abundant in the CA3/4 region of FTLD cases than in MND cases. Thus, although DPR distribution is not correlated with neurodegeneration spatially, it correlates with neuropathological subtypes. AU - Schludi, M.H.* AU - May, S.* AU - Grässer, F.A.* AU - Rentzsch, K.* AU - Kremmer, E. AU - Küpper, C.* AU - Klopstock, T.* AU - Arzberger, T.* AU - Edbauer, D.* C1 - 45471 C2 - 37344 SP - 537-555 TI - Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. JO - Acta Neuropathol. VL - 130 IS - 4 PY - 2015 SN - 0001-6322 ER - TY - JOUR AU - Schludi, M.H.* AU - May, S.* AU - Grässer, F.A.* AU - Rentzsch, K.* AU - Kremmer, E. AU - Küpper, C.* AU - Klopstock, T.* AU - German Consortium for Frontotemporal Lobar Degeneration (*) AU - Bavarian Brain Banking Alliance (*) AU - Arzberger, T.* AU - Edbauer, D.* C1 - 46654 C2 - 37684 SP - 557-558 TI - Erratum to: Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. JO - Acta Neuropathol. VL - 130 IS - 4 PY - 2015 SN - 0001-6322 ER - TY - JOUR AB - Heterozygous loss-of-function mutations in the progranulin (GRN) gene and the resulting reduction of GRN levels is a common genetic cause for frontotemporal lobar degeneration (FTLD) with accumulation of TAR DNA-binding protein (TDP)-43. Recently, it has been shown that a complete GRN deficiency due to a homozygous GRN loss-of-function mutation causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. These findings suggest that lysosomal dysfunction may also contribute to some extent to FTLD. Indeed, Grn(-/-) mice recapitulate not only pathobiochemical features of GRN-associated FTLD-TDP (FTLD-TDP/GRN), but also those which are characteristic for NCL and lysosomal impairment. In Grn(-/-) mice the lysosomal proteins cathepsin D (CTSD), LAMP (lysosomal-associated membrane protein) 1 and the NCL storage components saposin D and subunit c of mitochondrial ATP synthase (SCMAS) were all found to be elevated. Moreover, these mice display increased levels of transmembrane protein (TMEM) 106B, a lysosomal protein known as a risk factor for FTLD-TDP pathology. In line with a potential pathological overlap of FTLD and NCL, Ctsd(-/-) mice, a model for NCL, show elevated levels of the FTLD-associated proteins GRN and TMEM106B. In addition, pathologically phosphorylated TDP-43 occurs in Ctsd(-/-) mice to a similar extent as in Grn(-/-) mice. Consistent with these findings, some NCL patients accumulate pathologically phosphorylated TDP-43 within their brains. Based on these observations, we searched for pathological marker proteins, which are characteristic for NCL or lysosomal impairment in brains of FTLD-TDP/GRN patients. Strikingly, saposin D, SCMAS as well as the lysosomal proteins CTSD and LAMP1/2 are all elevated in patients with FTLD-TDP/GRN. Thus, our findings suggest that lysosomal storage disorders and GRN-associated FTLD may share common features. AU - Götzl, J.K.* AU - Mori, K.* AU - Damme, M.* AU - Fellerer, K.* AU - Tahirovic, S.* AU - Kleinberger, G.* AU - Janssens, J.* AU - van der Zee, J.* AU - Lang, C.M.* AU - Kremmer, E. AU - Martin, J.J.* AU - Engelborghs, S.* AU - Kretzschmar, H.A.* AU - Arzberger, T.* AU - van Broeckhoven, C.* AU - Haass, C.* AU - Capell, A.* C1 - 30844 C2 - 33949 CY - New York SP - 845-860 TI - Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. JO - Acta Neuropathol. VL - 127 IS - 6 PB - Springer PY - 2014 SN - 0001-6322 ER - TY - JOUR AB - Hexanucleotide repeat expansion in C9orf72 is the most common pathogenic mutation in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the lack of an ATG start codon, the repeat expansion is translated in all reading frames into dipeptide repeat (DPR) proteins, which form insoluble, ubiquitinated, p62-positive aggregates that are most abundant in the cerebral cortex and cerebellum. To specifically analyze DPR toxicity and aggregation, we expressed DPR proteins from synthetic genes containing a start codon but lacking extensive GGGGCC repeats. Poly-Gly-Ala (GA) formed p62-positive cytoplasmic aggregates, inhibited dendritic arborization and induced apoptosis in primary neurons. Quantitative mass spectrometry analysis to identify poly-GA co-aggregating proteins revealed a significant enrichment of proteins of the ubiquitin-proteasome system. Among the other interacting proteins, we identified the transport factor Unc119, which has been previously linked to neuromuscular and axonal function, as a poly-GA co-aggregating protein. Strikingly, the levels of soluble Unc119 are strongly reduced upon poly-GA expression in neurons, suggesting a loss of function mechanism. Similar to poly-GA expression, Unc119 knockdown inhibits dendritic branching and causes neurotoxicity. Unc119 overexpression partially rescues poly-GA toxicity suggesting that poly-GA expression causes Unc119 loss of function. In C9orf72 patients, Unc119 is detectable in 9.5 % of GA inclusions in the frontal cortex, but only in 1.6 % of GA inclusions in the cerebellum, an area largely spared of neurodegeneration. A fraction of neurons with Unc119 inclusions shows loss of cytosolic staining. Poly-GA-induced Unc119 loss of function may thereby contribute to selective vulnerability of neurons with DPR protein inclusions in the pathogenesis of C9orf72 FTLD/ALS. AU - May, S.* AU - Hornburg, D.* AU - Schludi, M.H.* AU - Arzberger, T.* AU - Rentzsch, K.* AU - Schwenk, B.M.* AU - Grässer, F.A.* AU - Mori, K.* AU - Kremmer, E. AU - Banzhaf-Strathmann, J.* AU - Mann, M.* AU - Meissner, F.* AU - Edbauer, D.* C1 - 31958 C2 - 34909 CY - New York SP - 485-503 TI - C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. JO - Acta Neuropathol. VL - 128 IS - 4 PB - Springer PY - 2014 SN - 0001-6322 ER - TY - JOUR AB - Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology. AU - van der Zee, J.* AU - van Langenhove, T.* AU - Kovacs, G.G.* AU - Dillen, L.* AU - Deschamps, W.* AU - Engelborghs, S.* AU - Matěj, R.* AU - Vandenbulcke, M.* AU - Sieben, A.* AU - Dermaut, B.* AU - Smets, K.* AU - van Damme, P.V.* AU - Merlin, C.* AU - Laureys, A.* AU - van den Broeck, M.V.* AU - Mattheijssens, M.* AU - Peeters, K.* AU - Benussi, L.* AU - Binetti, G.* AU - Ghidoni, R.* AU - Borroni, B.* AU - Padovani, A.* AU - Archetti, S.* AU - Pastor, P.* AU - Razquin, C.* AU - Ortega-Cubero, S.* AU - Hernández, I.* AU - Boada, M.* AU - Ruiz, A.* AU - de Mendonca, A.* AU - Miltenberger-Miltényi, G.* AU - do Couto, F.S.* AU - Sorbi, S.* AU - Nacmias, B.* AU - Bagnoli, S.* AU - Graff, C.* AU - Chiang, H.* AU - Thonberg, H.* AU - Perneczky, R.* AU - Diehl-Schmid, J.* AU - Alexopoulos, P.* AU - Frisoni, G.B.* AU - Bonvicini, C.* AU - Synofzik, M.* AU - Maetzler, W.* AU - Vom Hagen, J.M.* AU - Schöls, L.* AU - Haack, T.B. AU - Strom, T.M. AU - Prokisch, H. AU - Dols-Icardo, O.* AU - Clarimõn, J.* AU - Lleõ, A.* AU - Santana, I.* AU - Almeida, M.R.* AU - Santiago, B.* AU - Heneka, M.T.* AU - Jessen, F.* AU - Ramirez, A.* AU - Sánchez-Valle, R.* AU - Lladó, A.* AU - Gelpi, E.* AU - Sarafov, S.* AU - Tournev, I.* AU - Jordanova, A.* AU - Parobková, E.* AU - Fabrizi, G.M.* AU - Testi, S.* AU - Salmon, E.* AU - Ströbel, T.* AU - Santens, P.* AU - Robberecht, W.* AU - de Jonghe, P.* AU - Martín, J.J.R.* AU - Cras, P.* AU - Vandenberghe, R.R.C.* AU - de Deyn, P.P.* AU - Cruts, M.* AU - Sleegers, K.* AU - van Broeckhoven, C.L.* C1 - 31616 C2 - 34638 SP - 397-410 TI - Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. JO - Acta Neuropathol. VL - 128 IS - 3 PY - 2014 SN - 0001-6322 ER - TY - JOUR AB - Favorable outcome after chemotherapy of glioblastomas cannot unequivocally be linked to promoter hypermethylation of the O (6)-methylguanine-DNA methyltransferase (MGMT) gene encoding a DNA repair enzyme associated with resistance to alkylating agents. This indicates that molecular mechanisms determining MGMT expression have not yet been fully elucidated. We here show that glioblastomas are capable to downregulate MGMT expression independently of promoter methylation by elongation of the 3'-UTR of the mRNA, rendering the alternatively polyadenylated transcript susceptible to miRNA-mediated suppression. While the elongated transcript is poorly expressed in normal brain, its abundance in human glioblastoma specimens is inversely correlated with MGMT mRNA expression. Using a bioinformatically guided experimental approach, we identified miR-181d, miR-767-3p, and miR-648 as significant post-transcriptional regulators of MGMT in glioblastomas; the first two miRNAs induce MGMT mRNA degradation, the latter affects MGMT protein translation. A regression model including the two miRNAs influencing MGMT mRNA expression and the MGMT methylation status reliably predicts The Cancer Genome Atlas MGMT expression data. Responsivity of MGMT expressing T98G glioma cells to temozolomide was significantly enhanced after transfection of miR-181d, miR-767-3p, and miR-648. Taken together, our results uncovered alternative polyadenylation of the MGMT 3'-UTR and miRNA targeting as new mechanisms of MGMT silencing. AU - Kreth, S.* AU - Limbeck, E.* AU - Hinske, L.C.* AU - Schütz, S.V.* AU - Thon, N.* AU - Hoefig, K.P. AU - Egensperger, R.* AU - Kreth, F.W.* C1 - 24291 C2 - 31499 SP - 671-681 TI - In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing. JO - Acta Neuropathol. VL - 125 IS - 5 PB - Springer PY - 2013 SN - 0001-6322 ER - TY - JOUR AB - Gonadotroph adenomas comprise 15-40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demonstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepresentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinformatic analysis identified downstream targets of the transcription factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similarities between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadotroph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma primary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use. AU - Lee, M.S. AU - Marinoni, I. AU - Irmler, M. AU - Psaras, T.* AU - Honegger, J.B.* AU - Beschorner, R.* AU - Anastasov, N. AU - Beckers, J. AU - Theodoropoulou, M.* AU - Roncaroli, F.* AU - Pellegata, N.S. C1 - 24846 C2 - 31708 SP - 137-150 TI - Transcriptome analysis of MENX-associated rat pituitary adenomas identifies novel molecular mechanisms involved in the pathogenesis of human pituitary gonadotroph adenomas. JO - Acta Neuropathol. VL - 126 IS - 1 PB - Springer PY - 2013 SN - 0001-6322 ER - TY - JOUR AB - Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. Recently, unconventional non-ATG translation of the expanded hexanucleotide repeat, resulting in the production and aggregation of dipeptide repeat (DPR) proteins (poly-GA, -GR and GP), was identified as a potential pathomechanism of C9ORF72 mutations. Besides accumulation of DPR proteins, the second neuropathological hallmark lesion in C9ORF72 mutation cases is the accumulation of TDP-43. In this study, we characterized novel monoclonal antibodies against poly-GA and performed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in a cohort of 35 cases with the C9ORF72 mutation that included a broad spectrum of clinical phenotypes. We found the pattern of DPR pathology to be highly consistent among cases regardless of the phenotype with high DPR load in the cerebellum, all neocortical regions (frontal, motor cortex and occipital) and hippocampus, moderate pathology in subcortical areas and minimal pathology in lower motor neurons. No correlation between DPR pathology and the degree of neurodegeneration was observed, while a good association between TDP-43 pathology with clinical phenotype and degeneration in key anatomical regions was present. Our data confirm that the presence of DPR pathology is intimately related to C9ORF72 mutations. The observed dissociation between DPR inclusion body load and neurodegeneration might suggest inclusion body formation as a potentially protective response to cope with soluble toxic DPR species. Moreover, our data imply that alterations due to the C9ORF72 mutation resulting in TDP-43 accumulation and dysmetabolism as secondary downstream effects likely play a central role in the neurodegenerative process in C9ORF72 pathogenesis. AU - Mackenzie, I.R.* AU - Arzberger, T.* AU - Kremmer, E. AU - Troost, D.* AU - Lorenzl, S.* AU - Mori, K.* AU - Weng, S.M.* AU - Haass, C.* AU - Kretzschmar, H.A.* AU - Edbauer, D.* AU - Neumann, M.* C1 - 28694 C2 - 33524 SP - 859-879 TI - Dipeptide repeat protein pathology in C9ORF72 mutation cases: Clinico-pathological correlations. JO - Acta Neuropathol. VL - 126 IS - 6 PB - Springer PY - 2013 SN - 0001-6322 ER - TY - JOUR AB - Massive GGGGCC repeat expansion in the first intron of the gene C9orf72 is the most common known cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Despite its intronic localization and lack of an ATG start codon, the repeat region is translated in all three reading frames into aggregating dipeptide-repeat (DPR) proteins, poly-(Gly-Ala), poly-(Gly-Pro) and poly-(Gly-Arg). We took an antibody-based approach to further validate the translation of DPR proteins. To test whether the antisense repeat RNA transcript is also translated, we raised antibodies against the predicted products, poly-(Ala-Pro) and poly-(Pro-Arg). Both antibodies stained p62-positive neuronal cytoplasmic inclusions throughout the cerebellum and hippocampus indicating that not only sense but also antisense strand repeats are translated into DPR proteins in the absence of ATG start codons. Protein products of both strands co-aggregate suggesting concurrent translation of both strands. Moreover, an antibody targeting the putative carboxyl terminus of DPR proteins can detect inclusion pathology in C9orf72 repeat expansion carriers suggesting that the non-ATG translation continues through the entire repeat and beyond. A highly sensitive monoclonal antibody against poly-(Gly-Arg), visualized abundant inclusion pathology in all cortical regions and some inclusions also in motoneurons. Together, our data show that the GGGGCC repeat is bidirectionally translated into five distinct DPR proteins that co-aggregate in the characteristic p62-positive TDP-43 negative inclusions found in FTLD/ALS cases with C9orf72 repeat expansion. Novel monoclonal antibodies against poly-(Gly-Arg) will facilitate pathological diagnosis of C9orf72 FTLD/ALS. AU - Mori, K.* AU - Arzberger, T.* AU - Grässer, F.A.* AU - Gijselinck, I.* AU - May, S.* AU - Rentzsch, K.* AU - Weng, S.M.* AU - Schludi, M.H.* AU - van der Zee, J.* AU - Cruts, M.* AU - van Broeckhoven, C.* AU - Kremmer, E. AU - Kretzschmar, H.A.* AU - Haass, C.* AU - Edbauer, D.* C1 - 28698 C2 - 33521 SP - 881-893 TI - Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. JO - Acta Neuropathol. VL - 126 IS - 6 PB - Springer PY - 2013 SN - 0001-6322 ER - TY - JOUR AB - Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB(+1) accumulation, we used a UBB(+1) expressing transgenic mouse line that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer's disease (AD). In order to reveal affected organs and functions, young and aged UBB(+1) transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wild-type littermate mice. Accordingly, UBB(+1) was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus. In addition, UBB(+1) was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB(+1) expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients. AU - Irmler, M. AU - Gentier, R.J.* AU - Dennissen, F.J.* AU - Schulz, H. AU - Bolle, I. AU - Hölter, S.M. AU - Kallnik, M. AU - Cheng, J.J.* AU - Klingenspor, M.* AU - Rozman, J. AU - Ehrhardt, N. AU - Hermes, D.J.* AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Meyer, H.E.* AU - Hopkins, D.A.* AU - van Leeuwen, F.W.* AU - Beckers, J. C1 - 8209 C2 - 30046 SP - 187-197 TI - Long-term proteasomal inhibition in transgenic mice by UBB+1 expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients. JO - Acta Neuropathol. VL - 124 IS - 2 PB - Springer PY - 2012 SN - 0001-6322 ER - TY - JOUR AB - Dopaminergic (DA) neuron degeneration is a feature of brain aging but is markedly increased in patients with Parkinson's disease (PD). Recent data indicate elevated metabolic stress as a possible explanation for DA neuron vulnerability. Using laser capture microdissection, we isolated DA neurons from the substantia nigra pars compacta of PD patients, age-matched and young controls to determine transcriptional changes by expression profiling and pathway analysis. We verified our findings by comparison to a published dataset. Parallel processing of isolated neurons and bulk tissue allowed the discrimination of neuronal and glial transcription signals. Our data show that genes known to be involved in neural plasticity, axon and synaptic function, as well as cell fate are differentially regulated in aging DA neurons. The transcription patterns in aging suggest a largely maintained expression of genes in energy-related pathways in surviving neurons, possibly supported by the mediation of PPAR/RAR and CREB signaling. In contrast, a profound down-regulation of genes coding for mitochondrial and ubiquitin-proteasome system proteins was seen in PD when compared to the age-matched controls. This is in accordance with the established mitochondrial dysfunction in PD and provides evidence for mitochondrial impairment at the transcriptional level. In addition, the PD neurons had disrupted pathways that comprise a network involved in the control of energy metabolism and cell survival in response to growth factors, oxidative stress, and nutrient deprivation (PI3K/Akt, mTOR, eIF4/p70S6K and Hif-1α). PI3K/Akt and mTOR signaling are central hubs of this network which is of relevance to longevity and-together with induction of mitochondrial biogenesis-may constitute potential targets for therapeutic intervention. AU - Elstner, M. AU - Morris, C.M.* AU - Heim, K. AU - Bender, A.* AU - Mehta, D. AU - Jaros, E.* AU - Klopstock, T.* AU - Meitinger, T. AU - Turnbull, D.M.* AU - Prokisch, H. C1 - 5144 C2 - 28568 SP - 75-86 TI - Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death. JO - Acta Neuropathol. VL - 122 IS - 1 PB - Springer PY - 2011 SN - 0001-6322 ER - TY - JOUR AB - Accumulation of hyperphosphorylated, ubiquitinated and N-terminally truncated TAR DNA-binding protein (TDP-43) is the pathological hallmark lesion in most familial and sporadic forms of FTLD-U and ALS, which can be subsumed as TDP-43 proteinopathies. In order to get more insight into the role of abnormal phosphorylation in the disease process, the identification of specific phosphorylation sites and the generation of phosphorylation-specific antibodies are mandatory. Here, we developed and characterized novel rat monoclonal antibodies (1D3 and 7A9) raised against phosphorylated S409/410 of TDP-43. These antibodies were used to study the presence of S409/410 phosphorylation by immunohistochemistry and biochemical analysis in a large series of 64 FTLD-U cases with or without motor neuron disease including familial cases with mutations in progranulin (n = 5), valosin-containing protein (n = 4) and linkage to chromosome 9p (n = 4), 18 ALS cases as well as other neurodegenerative diseases with concomitant TDP-43 pathology (n = 5). Our data demonstrate that phosphorylation of S409/410 of TDP-43 is a highly consistent feature in pathologic inclusions in the whole spectrum of sporadic and familial forms of TDP-43 proteinopathies. Physiological nuclear TDP-43 was not detectable with these mAbs by immunohistochemistry and by immunoblot analyses. While the accumulation of phosphorylated C-terminal fragments was a robust finding in the cortical brain regions of FTLD-U and ALS, usually being much more abundant than the phosphorylated full-length TDP-43 band, spinal cord samples revealed a predominance of full-length TDP-43 over C-terminal fragments. This argues for a distinct TDP-43 species composition in inclusions in cortical versus spinal cord cells. Overall, these mAbs are powerful tools for the highly specific detection of disease-associated abnormal TDP-43 species and will be extremely useful for the neuropathological routine diagnostics of TDP-43 proteinopathies and for the investigation of emerging cellular and animal models for TDP-43 proteinopathies. AU - Neumann, M.* AU - Kwong, L.K.* AU - Lee, E.B.* AU - Kremmer, E. AU - Flatley, A. AU - Xu, Y.* AU - Forman, M.S.* AU - Troost, D.* AU - Kretzschmar, H.A.* AU - Trojanowski, J.Q AU - Lee, V.M.Y.* C1 - 2017 C2 - 26516 SP - 137-149 TI - Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. JO - Acta Neuropathol. VL - 117 IS - 2 PB - Springer PY - 2009 SN - 0001-6322 ER - TY - JOUR AB - D44 antigen (CD44), the principle cell surface receptor for hyaluronate, is up-regulated in the human demyelinating disease multiple sclerosis on fibrous astrocytes. As astrocytes are the main target cell of canine distemper virus (CDV). the consequences of a CDV infection on the CD44 expression and distribution in brains with spontaneous demyelinating canine distemper encephalitis (CDE) were of interest. Thirteen acute, 35 subacute, and 11 chronic plaques of nine dogs with immunohistologically confirmed CDE and brains of control dogs were included in the study. For light microscopy, 5-mu m-thick serial sections were stained with H&E and incubated with monoclonal antibodies (mAbs) against CD44 and canine distemper virus nucleoprotein and polyclonal antibodies (pAbs) against glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP). For immunoelectron microscopy, 90-nm-thick sections were double stained with anti-GFAP and anti-CD44 mAbs to specify CD44-expressing structures. In controls, CD44 was diffusely distributed in the white matter and single meningeal cells exhibited a marginal expression of the antigen. In acute and more prominently in subacute demyelinating encephalitis, there was a plaque-associated up-regulation of CD44 which paralleled GFAP. In chronic demyelinating lesions, a reduction of CD44 associated with a loss of GFAP-positive astrocytes was noted. Additionally, in chronic plaques, CD44 was expressed on the cell membrane of perivascular mononuclear cells. Immunoelectron microscopically, in controls, CD44 was rarely demonstrated on astrocytic cell processes. In contrast, in brains with CDE CD44 was found on the cell membrane of broadened astrocytic cell processes. In summary, CD44 is up-regulated on astrocytes in the early phase of CDE and seems to represent a marker for the activation of immune cells in the late phase of the infection. AU - Alldinger, S.* AU - Fonfara, S.* AU - Kremmer, E. AU - Baumgärtner, W.* C1 - 10397 C2 - 19335 SP - 138-146 TI - Up-regulation of the hyaluronate receptor CD44 in canine distemper demyelinated plaques. JO - Acta Neuropathol. VL - 99 PB - Springer PY - 2000 SN - 0001-6322 ER - TY - JOUR AB - We studied a 27-year-old woman who died after a 6-year history of progressive dementia, dystonia, ataxia, apraxia, spasticity, choreoathetosis, visual and auditory hallucinations, and optic atrophy. Magnetic resonance imaging showed decreased intensity in the globus pallidus, substantia nigra, and dentate nuclei in T2-weighted images, supporting the clinical diagnosis of neurodegeneration with brain iron accumulation type 1 (NBIA-1; formerly known as Hallervorden-Spatz syndrome). At autopsy the brain showed mild frontotemporal atrophy and discoloration of the globus pallidus and the substantia nigra pars reticularis. Histologically, features typical of NBIA-1 were found including widespread axonal spheroids and large deposits of iron pigment in the discolored regions. Additionally, excessive numbers of Lewy bodies (LBs) were found throughout all examined brain stem and cortical regions. LBs of both types, as well as Lewy neurites in this case of NBIA-1, were strongly labeled by antibodies against α-synuclein. These findings give further evidence that accumulation of α-synuclein is generally associated with LB formation, i.e., in Parkinson’s disease, dementia with Lewy bodies and NBIA-1. The case presented here is particularly notable for its high number of LBs in all areas of the cerebral cortex. AU - Neumann, M.* AU - Adler, S.* AU - Schlüter, O.* AU - Kremmer, E. AU - Benecke, R.* AU - Kretschmar, H.A.* C1 - 21608 C2 - 19739 SP - 568-574 TI - alpha-Synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. JO - Acta Neuropathol. VL - 100 IS - 5 PY - 2000 SN - 0001-6322 ER - TY - JOUR AB - he mouse Small eye (Sey) locus is situated on chromosome 2. Molecular analyses have shown that SeyNeu represents a point mutation leading to a splice site error and loss of the functional gene product. The Sey locus has been shown to be identical with the paired box (Pax)-6 gene, which contains paired-like and homcobox domains and is a developmental control gene. Pax-6 expression occurs in many parts of the central nervous system during embryogenesis. Therefore, we may expect the Sey mutation to result in abnormal development of the central nervous system. The present study shows that Pax-6 mutation has a bimodal effect upon neurogenesis in mouse: it causes a delay of premigratory neurons in a stage-, region-, and genedose-dependent manner. Additionally, Sey mutation impairs axonal growth and differentiation. Neurons of the cortical plate cease differentiation on approximately day 16 of gestation and appear to have increased cohesion: their cytoplasm is swollen and vacuolated. These changes coincide both with reduced formation of axons and with the onset of vacuolar degeneration in existing axons, glial cells and radial glial fibers. Consequently, there is an impairment of the peripheral migration of putative neurons so that the neonatal lesion pattern of the neocortical roof becomes dominated by a broad spectrum of neuronal migration disorders. AU - Schmahl, W. AU - Knödlseder, M. AU - Favor, J. AU - Davidson, D. C1 - 20686 C2 - 13904 SP - 126-135 TI - Defects of Neuronal Migration and the Phatogenesis of Cortical Malformations are associated with Small eye (Sey) in the Mouse, a Point Mutation at the Pax-6-locus. JO - Acta Neuropathol. VL - 86 IS - 2 PY - 1993 SN - 0001-6322 ER - TY - JOUR AB - The mouse Small eye (Sey) locus is situated on chromosome 2. Molecular analyses have shown that SeyNeu represents a point mutation leading to a splice site error and loss of the functional gene product. The Sey locus has been shown to be identical with the paired box (Pax)-6 gene, which contains paired-like and homcobox domains and is a developmental control gene. Pax-6 expression occurs in many parts of the central nervous system during embryogenesis. Therefore, we may expect the Sey mutation to result in abnormal development of the central nervous system. The present study shows that Pax-6 mutation has a bimodal effect upon neurogenesis in mouse: it causes a delay of premigratory neurons in a stage-, region-, and genedose-dependent manner. Additionally, Sey mutation impairs axonal growth and differentiation. Neurons of the cortical plate cease differentiation on approximately day 16 of gestation and appear to have increased cohesion: their cytoplasm is swollen and vacuolated. These changes coincide both with reduced formation of axons and with the onset of vacuolar degeneration in existing axons, glial cells and radial glial fibers. Consequently, there is an impairment of the peripheral migration of putative neurons so that the neonatal lesion pattern of the neocortical roof becomes dominated by a broad spectrum of neuronal migration disorders. AU - Schmahl, W.G. AU - Knoedlseder, M. AU - Favor, J. AU - Davidson, D.R.* C1 - 40343 C2 - 40056 SP - 126-135 TI - Defects of neuronal migration and the pathogenesis of cortical malformations are associated with Small eye (Sey) in the mouse, a point mutation at the Pax-6-locus. JO - Acta Neuropathol. VL - 86 IS - 2 PY - 1993 SN - 0001-6322 ER - TY - JOUR AB - Purified McAbs (14AC1) of IgG2a isotype raised against an experimental rat glioma (79 FR-G-41) were labeled with Na131I and used for in vivo imaging of glioma grafts by external body seintigraphy. Normal mouse131I-IgG was applied as control for non-specific uptake of proteins in the tumor. Nude mice bearing glioma grafts were injected i.v. with 15 μg of the131I-McAb or131I-IgG with an activity of approximately 150 μCi. Scands obtained 30 min, 24, 48, 72, and 96 h after injecting the intact131I-14AC1 antibody demonstrated enrichment of radioactivity in the tumors. The tumors were clearly visible 48 h after injection of131I-labeled antibody. The time course experiments showed that the uptake of131I-14AC1 antibody in the glioma grafts was the result of specific antigen binding. Intact antibody provided adequate tumor visualization in the scientigrams without background subtraction. Therefore, this technique appears promising for in vivo tumor detection and may offer the possibility of improvement in the evaluation of diagnostic and therapeutic approaches to human gliomas. AU - Stavrou, D.K.* AU - Mellert, W.* AU - Bilzer, T.W.* AU - Senekowitsch, R. AU - Keiditsch, E.* AU - Mehraein, P.* C1 - 40894 C2 - 38358 SP - 340-342 TI - Localization of experimental glioma grafts by means of iodinated monoclonal antibodies and radionuclide imaging. JO - Acta Neuropathol. VL - 66 IS - 4 PY - 1985 SN - 0001-6322 ER -