Cerebellar transcriptional alterations with Purkinje cell dysfunction and loss in mice lacking PGC-1α

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.

Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice

“…In particular, the function of or-gans with high energy demands such as brain depends on flawless mitochondrial operation for their optimal performance. Mitochondrial defects have been reported as a cause for many neurodegenerative diseases (Johri and Beal, 2012) such as Alzheimer's disease (Moreira et al, 2010), Parkinson's disease (Winklhofer and Haass, 2010), Huntington's disease (Quintanilla and Johnson, 2009), Friedreich ataxia (Delatycki et al, 2000), and other spinocerebellar ataxias (Zeviani et al, 2012).…”

“…Octanoic acid is a confirmed product of mtFAS and required as a precursor for endogenous synthesis of lipoic acid (LA). In Saccharomyces cerevisiae, the inactivation of any of the enzymes of mtFAS leads to respiratory defects, lack of cytochromes due to disturbed mitochondrial translation and respiratory complex assembly, rudimentary mitochondria and loss of protein lipoylation (Kastaniotis et al, 2004;Kursu et al, 2013). Evidence generated in yeast and mammalian models indicates that, in addition to providing the LA precursor, mtFAS products play important roles in mitochondrial biogenesis, affecting heme biosynthesis, regulating respiratory chain assembly (Kursu et al, 2013, Zhu et al, 2015, Van Vranken et al, 2018, and participating in iron-sulfur (Fe-S) cluster biosynthesis (Van Vranken et al, 2016, Cory et al, 2017.…”

“…Mitochondrial enoyl-CoA/ACP reductase (MECR) catalyzes the NADPH-dependent reduction of enoyl ACP to saturated acyl-ACP (Miinalainen et al, 2003). This is the last enzyme of mtFAS pathway and essential for embryonic development in mouse (Nair et al, 2017). Mutations in the MECR orthologs in human were recently reported to result in a neurodegenerative disease termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration), which is characterized by symptoms like hypotonia, dysarthria and visual impairment in patients (Heimer et al, 2016).…”

Gait analysis in a mouse model resembling Leigh disease

“…The automated CatWalk gait analysis method is also applied in models involving other types of pain and peripheral nerve damage and movement disorders like Parkinson's disease [21][22][23]. Abnormal gait was described in mice exhibiting (cerebellar) ataxia, by using paw print area, contact area, base of support of the hindpaws, stand, swing and step regularity [24][25][26]. The aim of this study was to identify gait changes in the Ndufs4 −/− mouse by using the CatWalk system.…”

Neuropathological characterization of FL-PGC-1α-deficient mice – implications for mitochondrial encephalopathy

“…Notably, an independent group performing parallel examinations on the complete PGC-1α -/-strain recently reported no significant reduction in the number of MSNs in the knockout animals [146], supporting our observations. By contrast, during the preparation of our manuscript, the same group reported a significant loss of cerebellar Purkinje neurons in PGC-1α -/-mice by stereological methods [147], which is striking, as this feature is virtually pathognomonic of KSS. This observation independently (and unintentionally) confirms our concept.…”