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

NEUROBIOLOGY OF DISEASE

卷:121

Article

Soyal, Selma M.¹  Zara, Greta¹  Ferger, Boris²  Felder, Thomas K.³  Kwik, Markus¹  Nofziger, Charity¹  Dossena, Silvia¹  Schwienbacher, Christine⁴  Hicks, Andrew A.⁴  Pramstaller, Peter P.⁴  Paulmichl, Markus⁵  Weis, Serge⁶  Patsch, Wolfgang¹ 

[1] Paracelsus Med Univ, Inst Pharmacol & Toxicol, Strubergasse 21, A-5020 Salzburg, Austria

[2] Boehringer Ingelheim Pharma GmbH & Co KG, Biberachan, Germany

[3] Paracelsus Med Univ, Dept Lab Med, Salzburg, Austria

[4] Univ Lubeck, Affiliated Inst, Eurac Res, Inst Biomed, Bolzano, Italy

[5] Austrian Inst Technol, Ctr Hlth & Bioresources, Vienna, Austria

[6] Johannes Kepler Univ Hosp, Div Neuropathol, Linz, Austria

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

DOI  :  10.1016/j.nbd.2018.09.016

来源: Elsevier

【 摘 要 】

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. PGC-1 alpha, 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-1 alpha 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】

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