A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice

Abstract

PGC1α is a transcriptional coactivator in peripheral tissues, but its function in the brain remains poorly understood. Various brain-specific Pgc1α isoforms have been reported in mice and humans, including two fusion transcripts (FTs) with non-coding repetitive sequences, but their function is unknown. The FTs initiate at a simple sequence repeat locus ∼570 Kb upstream from the reference promoter; one also includes a portion of a short interspersed nuclear element (SINE). Using publicly available genomics data, here we show that the SINE FT is the predominant form of Pgc1α in neurons. Furthermore, mutation of the SINE in mice leads to altered behavioural phenotypes and significant up-regulation of genes in the female, but not male, cerebellum. Surprisingly, these genes are largely involved in neurotransmission, having poor association with the classical mitochondrial or antioxidant programs. These data expand our knowledge on the role of Pgc1α in neuronal physiology and suggest that different isoforms may have distinct functions. They also highlight the need for further studies before modulating levels of Pgc1α in the brain for therapeutic purposes.

Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging

“…Focusing on established targets of PGC-1a transcriptional co-activation, a suite of genes associated with the electron transport chain (Cox4i1, Ndiufb8, Cycs, Vdac1, Cox5b), TCA cycle (Sdhb, Idh3a), and antioxidant maintenance (Sod2 and Cat) appear downregulated in response to LiCl, while expression of other PGC-1a associated factors including Nrf1, Ppara, Ucp2 were induced (Fig.5D). Genes associated with the neuronal function (Syt1 and Cplx1 (Lozoya et al, 2021) appear to be the most down-regulated, supporting PGC-1a B1E2’s role in modulating neuron-specific functions (Lozoya et al, 2021). A significant increase in BDNF expression, a neurotrophic factor important for neuronal health was also detected, and although BDNF is linked to PGC-1a levels and activation status at least in skeletal muscle (Wrann et al, 2013), these data suggest that the neuronal PGC-1a B1E2 isoform may be independent of BDNF.…”

“…5D). Genes associated with the neuronal function (Syt1 and Cplx1 (Lozoya et al, 2021) appear to be the most downregulated, supporting PGC-1a B1E2's role in modulating neuron-specific functions (Lozoya et al, 2021). A significant increase in BDNF expression, a neurotrophic factor important for neuronal health was also detected, and although BDNF is linked to PGC-1a levels and activation status at least in skeletal muscle (Wrann et al, 2013), these data suggest that the neuronal PGC-1a B1E2 isoform may be independent of BDNF.…”

“…Neuronal metabolic status aligns with expression from the brain-specific promoter, indicating a functional dominance of this isoform. Genetic studies of PGC-1a B1E2 indicate that it regulates a suite of neuron-specific genes (e.g., neurotransmitter pathways) (Lozoya et al, 2021; Ruas et al, 2012), expanding its sphere of influence beyond energetics specifically in this cell type. In mice, PGC-1a was previously linked to arborization in neurons of the hippocampus (Cheng et al, 2012) and maintenance of the neuromuscular junction in skeletal muscle (Handschin et al, 2007), possibly secondary to its effects on mitochondria.…”

“…There are multiple isoforms of PGC-1a derived from distinct promoter regions of the Ppargc-1a gene (Martínez-Redondo et al, 2015). The promoters are activated in response to different physiological stimuli (Ruas et al, 2012; Soyal et al, 2020), and the resulting protein isoforms appear to have both common and isoform specific gene targets (Lozoya et al, 2021; Martínez-Redondo et al, 2015; Ruas et al, 2012). For example, in skeletal muscle, PGC-1a transcript variants expressed off the alternative promoter are selectively induced by resistance exercise, while the canonical promoter is activated by endurance exercise (Ruas et al, 2012).…”

Reversal of neuronal tau pathology, metabolic dysfunction, and electrophysiological defects via adiponectin pathway-dependent AMPK activation

“…Effects of AD pathology on mitochondrial function, specifically in the neuron, are less well categorized. PGC-1a is a transcriptional coactivator and master regulator of mitochondrial function that has been indirectly linked to broader cellular processes in diverse cell types, including redox metabolism, cell cycle and cell size determination, arborization, and hypertrophy 31,[52][53][54] . Three promotor regions in the Ppargc-1a gene are active in neurons, including one that is neuron-specific 54 , yielding three transcript variants of PGC-1a.…”