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Elstner, M. ; Morris, C.M.* ; Heim, K. ; Bender, A.* ; Mehta, D. ; Jaros, E.* ; Klopstock, T.* ; Meitinger, T. ; Turnbull, D.M.* ; Prokisch, H.

Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death.

Acta Neuropathol. 122, 75-86 (2011)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Parkinson’s disease; Aging; Dopaminergic neuron; Glia; Gene expression; Pathway analysis; Mitochondria; Energy metabolism; PI3K/Akt; mTOR; Hif-1a
Sprache englisch
Veröffentlichungsjahr 2011
HGF-Berichtsjahr 2011
ISSN (print) / ISBN 0001-6322
e-ISSN 1432-0533
Zeitschrift Acta Neuropathologica
Quellenangaben Band: 122, Heft: 1, Seiten: 75-86 Artikelnummer: , Supplement: ,
Verlag Springer
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
PubMed ID 21541762
DOI 10.1007/s00401-011-0828-9
Scopus ID 79959602140
Erfassungsdatum 2011-06-29
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