| First Author | Soyal SM | Year | 2019 |
| Journal | Neurobiol Dis | Volume | 121 |
| Pages | 34-46 | PubMed ID | 30236862 |
| Mgi Jnum | J:268600 | Mgi Id | MGI:6267194 |
| Doi | 10.1016/j.nbd.2018.09.016 | Citation | Soyal SM, et al. (2019) The PPARGC1A locus and CNS-specific PGC-1alpha isoforms are associated with Parkinson's Disease. Neurobiol Dis 121:34-46 |
| abstractText | Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. PGC-1alpha, 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 17kDa 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 17kDa proteins that inhibited the co-activation of several transcription factors by full-length PGC-1alpha 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. |
