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

• Published in: Neurobiology of disease 2019-01, Vol.121, p.34-46
• Main Authors: Soyal, Selma M., Zara, Greta, Ferger, Boris, Felder, Thomas K., Kwik, Markus, Nofziger, Charity, Dossena, Silvia, Schwienbacher, Christine, Hicks, Andrew A., Pramstaller, Peter P., Paulmichl, Markus, Weis, Serge, Patsch, Wolfgang
• Format: Article
• Language: English
• Subjects: haplotypes; Lewy body dementia; Parkinson's disease; PGC-1α; PPARGC1A
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2018.09.016

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. •CNS-PPARGC1A transcripts encoding full-length proteins were reduced in substantia nigra of Parkinson’s disease (PD) cases•CNS-PPARGC1A transcripts encoding 17 kDa isoforms were increased in the substantia nigra and globus pallidus of PD cases•The 17 kDa proteins inhibited the co-activation of HNF4α and PPARγ by full-length PGC-1α isoforms•CNS-PPARGC1A haplotypes protected against PD in two populations with comparable geographic and ethnic backgrounds