Abstract
Alterations in the expression and activity of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (ppargc1a or PGC-1α) have been reported in multiple movement disorders, yet it is unclear how a lack of PGC-1α impacts transcription and function of the cerebellum, a region with high PGC-1α expression. We show here that mice lacking PGC-1α exhibit ataxia in addition to the previously described deficits in motor coordination. Using q-RT-PCR in cerebellar homogenates from PGC-1α−/− mice, we measured expression of 37 microarray-identified transcripts upregulated by PGC-1α in SH-SY5Y neuroblastoma cells with neuroanatomical overlap with PGC-1α or parvalbumin (PV), a calcium buffer highly expressed by Purkinje cells. We found significant reductions in transcripts with synaptic (complexin1, Cplx1; Pacsin2), structural (neurofilament heavy chain, Nefh), and metabolic (isocitrate dehydrogenase 3a, Idh3a; neutral cholesterol ester hydrolase 1, Nceh1; pyruvate dehydrogenase alpha 1, Pdha1; phytanoyl-CoA hydroxylase, Phyh; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1, Uqcrfs1) functions. Using conditional deletion of PGC-1α in PV-positive neurons, we determined that 50% of PGC-1α expression and a reduction in a subset of these transcripts could be explained by its concentration in PV-positive neuronal populations in the cerbellum. To determine whether there were functional consequences associated with these changes, we conducted stereological counts and spike rate analysis in Purkinje cells, a cell type rich in PV, from PGC-1α−/− mice. We observed a significant loss of Purkinje cells by 6 weeks of age, and the remaining Purkinje cells exhibited a 50% reduction in spike rate. Together, these data highlight the complexity of PGC-1α's actions in the central nervous system and suggest that dysfunction in multiple cell types contribute to motor deficits in the context of PGC-1α deficiency.
Highlights
Given the high expression of PGC-1α in the cerebellum compared to other brain regions (Cowell et al, 2007), we hypothesized that motor impairment in PGC-1α−/− animals would include ataxia and conducted CatWalk gait analyses on male PGC-1α+/+ and −/− littermates at 6 months of age
In this manuscript, we present data showing that mice lacking PGC-1α exhibit a behavioral phenotype indicative of cerebellar dysfunction and show reduced cerebellar expression of transcripts involved in synaptic (Cplx1, Pacsin2), structural (Nefh), and metabolic (Idh3a, Nceh1, Pdha1, Phyh, and Uqcrfs1) functions
Using mice expressing Cre recombinase under the control of the PV promoter, we postnatally ablated PGC-1α in neuronal types enriched in its expression and observed reduced transcript expression of PGC-1α and its dependent genes complexin 1 (Cplx1), neurofilament heavy chain (Nefh), Idh3a, and Uqcrsf1, suggesting that PGC-1α regulation of these transcripts is specific to Purkinje cells, interneurons of the cerebellar cortex, and neurons of the deep cerebellar nuclei (Supplementary Table 4)
Summary
Since the identification of peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) as a master regulator of mitochondrial biogenesis in brown adipose tissue (Puigserver et al, 1998), a number of studies have demonstrated an association between PGC-1α dysfunction and neurological disorders, including Huntington Disease (Cui et al, 2006; Weydt et al, 2006; Chaturvedi et al, 2010; Hathorn et al, 2011; Johri et al, 2012; Puddifoot et al, 2012; Soyal et al, 2012), Parkinson Disease (StPierre et al, 2006; Zheng et al, 2010; Clark et al, 2011; Shin et al, 2011; Thomas et al, 2012), and Alzheimer Disease (Qin et al, 2009; Sheng et al, 2012; Pedros et al, 2014). We recently determined that in GAD67-positive interneurons of the cortex, PGC-1α is involved in regulating the calcium buffer parvalbumin (PV), the synaptic proteins synaptogamin 2 (Syt2) and complexin 1 (Cplx1), and the structural protein neurofilament heavy chain (Nefh; Lucas et al, 2010, 2014). These data indicate that PGC-1α can drive genes besides those involved in metabolic regulation and that PGC-1α’s role in neurons may be more complex than previously appreciated
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