PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Mackenzie, I.R.* ; Arzberger, T.* ; Kremmer, E. ; Troost, D.* ; Lorenzl, S.* ; Mori, K.* ; Weng, S.M.* ; Haass, C.* ; Kretzschmar, H.A.* ; Edbauer, D.* ; Neumann, M.*

Dipeptide repeat protein pathology in C9ORF72 mutation cases: Clinico-pathological correlations.

Acta Neuropathol. 126, 859-879 (2013)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
9.734
2.162
229
242
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter C9orf72 ; Motor Neuron Disease ; Frontotemporal Dementia ; Tdp-43 ; Non-atg Translation; Amyotrophic-lateral-sclerosis ; Frontotemporal Lobar Degeneration ; Hexanucleotide Repeat ; Clinical Characteristics ; Chromosome 9p ; Ggggcc Repeat ; Expansion ; Dementia ; Features ; Tdp-43
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0001-6322
e-ISSN 1432-0533
Zeitschrift Acta Neuropathologica
Quellenangaben Band: 126, Heft: 6, Seiten: 859-879 Artikelnummer: , Supplement: ,
Verlag Springer
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Immunology (IMI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501793-001
PubMed ID 24096617
DOI 10.1007/s00401-013-1181-y
WOS ID WOS:000327100500007
Scopus ID 84892611020
Erfassungsdatum 2013-12-13
[➜Korrektur melden]