The PPARGC1A locus and CNS-specific PGC-1α isoforms are associated with Parkinson's Disease

Neurobiology of Disease

卷:121

Markus Kwik¹  Greta Zara²  Thomas K. Felder³  Wolfgang Patsch⁴  Charity Nofziger⁵  Markus Paulmichl⁶  Serge Weis⁶  Peter P. Pramstaller⁶  Christine Schwienbacher⁷  Andrew A. Hicks⁷  Boris Ferger⁷  Silvia Dossena⁷  Selma M. Soyal⁷ 

[1] Co. KG, Biberachan der Riss, Germany;

[2] Corresponding authors at: Institute of Pharmacology and Toxicology, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.;

[3] Boehringer Ingelheim Pharma GmbH &

[4] Center for Health &

[5] Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria;

[6] Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy;

[7] Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria;

关键词: Parkinson's disease;    Lewy body dementia;    PPARGC1A;    PGC-1α;    haplotypes;   

DOI  :  

来源: DOAJ

【 摘 要 】

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. PGC-1α, encoded by PPARGC1A, is a transcriptional co-activator that has been implicated in the pathogenesis of neurodegenerative disorders. We recently discovered multiple new PPARGC1A transcripts that initiate from a novel promoter located far upstream of the reference gene promoter, are CNS-specific and are more abundant than reference gene transcripts in whole brain. These CNS-specific transcripts encode two main full-length and several truncated isoforms via alternative splicing. Truncated CNS-isoforms include 17 kDa proteins that lack the second LXXLL motif serving as an interaction site for several nuclear receptors. We now determined expression levels of CNS- and reference gene transcripts in 5 brain regions of 21, 8, and 13 deceased subjects with idiopathic PD, Lewy body dementia and controls without neurodegenerative disorders, respectively. We observed reductions of CNS-specific transcripts (encoding full-length isoforms) only in the substantia nigra pars compacta of PD and Lewy body dementia. However, in the substantia nigra and globus pallidus of PD cases we found an up-regulation of transcripts encoding the 17 kDa proteins that inhibited the co-activation of several transcription factors by full-length PGC-1α proteins in transfection assays. In two established animal models of PD, the PPARGC1A expression profiles differed from the profile in human PD in that the levels of CNS- and reference gene transcripts were decreased in several brain regions. Furthermore, we identified haplotypes in the CNS-specific region of PPARGC1A that appeared protective for PD in a clinical cohort and a post-mortem sample (P = .0002). Thus, functional and genetic studies support a role of the CNS-specific PPARGC1A locus in PD.

【 授权许可】

Unknown