Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

Abstract

Substantial evidence indicates that mitochondrial impairment contributes to neuronal dysfunction and vulnerability in disease states, leading investigators to propose that the enhancement of mitochondrial function should be considered a strategy for neuroprotection. However, multiple attempts to improve mitochondrial function have failed to impact disease progression, suggesting that the biology underlying the normal regulation of mitochondrial pathways in neurons, and its dysfunction in disease, is more complex than initially thought. Here, we present the proteins and associated pathways involved in the transcriptional regulation of nuclear-encoded genes for mitochondrial function, with a focus on the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). We highlight PGC-1α’s roles in neuronal and non-neuronal cell types and discuss evidence for the dysregulation of PGC-1α-dependent pathways in Huntington’s Disease, Parkinson’s Disease, and developmental disorders, emphasizing the relationship between disease-specific cellular vulnerability and cell-type-specific patterns of PGC-1α expression. Finally, we discuss the challenges inherent to therapeutic targeting of PGC-1α-related transcriptional programs, considering the roles for neuron-enriched transcriptional coactivators in co-regulating mitochondrial and synaptic genes. This information will provide novel insights into the unique aspects of transcriptional regulation of mitochondrial function in neurons and the opportunities for therapeutic targeting of transcriptional pathways for neuroprotection.

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model

“…Early studies of PGC-1α identified its thermogenic role in skeletal muscle and brown fat, by uncoupling mitochondrial respiration in response to cold (Puigserver et al, 1998); interestingly, cold does not induce PGC-1α in the brain. There, its role may relate to protection against other stresses, including cytokines and lipopolysaccharides (McMeekin et al, 2021; Puigserver et al, 2001). For instance, PGC-1α leads to increases in expression of various enzymes involved in detoxification of reactive oxygen species (Austin and St-Pierre, 2012).…”

“…Studies in non-neuronal tissue have identified the transcriptional coactivator, PGC-1α (peroxisome proliferator activated receptor gamma coactivator 1α), as a key regulator of expression of nuclear encoded mitochondrial genes (Austin and St-Pierre, 2012; Handschin and Spiegelman, 2006; Lin et al, 2005; McMeekin et al, 2021). Its expression is induced by various triggers, including exercise, cold and fasting, and it then drives mitochondrial (Puigserver et al, 2001) and peroxisome biogenesis (Bagattin et al, 2010) and uncouples mitochondrial respiration (St-Pierre et al, 2003).…”

“…These various considerations – their apparent high metabolism, and the powerful effect that PV interneurons exert upon cortical networks – have led to the suggestion that PV interneurons may be particularly susceptible to metabolic stress, which in turn could give rise to neuropathology (Kann, 2016; Whittaker et al, 2011). It is relevant, therefore, that reduced PGC-1α expression has been found in a number of neurological conditions (McMeekin et al, 2021), including Parkinson’s disease (Zheng et al, 2010), Alzheimer’s disease (Qin et al, 2009; Sheng et al, 2012), Huntington’s disease (Cui et al, 2006), multiple sclerosis (Witte et al, 2013), and schizophrenia (Christoforou et al, 2007; Jiang et al, 2013a), but interestingly, not epilepsy. Germline knockdown of PGC-1α is associated with hyperactive behaviour (Lin et al, 2004), although this is believed to be a behavioural adaptation to a reduction in thermogenesis capacity in brown fat and muscle, because the hyperactive phenotype was not replicated in mice with central nervous system deletion of PGC-1α (Lucas et al, 2012).…”

The Role of PGC1α in Alzheimer’s Disease and Therapeutic Interventions

“…Since the early 2000s, PGC1α has attracted interest because of its important role in metabolic processes (including gluconeogenesis, glucose transport, and fatty acid oxidation), mitochondrial biogenesis, peroxisomal remodelling, and detoxification of reactive oxygen species (ROS) [2]. These effects are mediated through the regulation of a number of transcription factors, including nuclear respiratory factors (NFRs) NRF-1 and NRF-2 (interacting with Tfam, which drives transcription and replication of mtDNA), PPARs (PPARα, PPARδ/β, and PPARγ), thyroid hormone, glucocorticoid, oestrogen, and ERRs (oestrogen-related receptors) α and γ [3] (ERRα, ERRβ, and ERRγ), initiator element binding factor (YY1), myocyte-specific enhancer factors (MEF-2A, MEF-2C, MEF-2D), forkhead box O1 (FOXO1), and others [4].…”

The master energy homeostasis regulator PGC-1α couples transcriptional co-activation and mRNA nuclear export

“…It is predominantly expressed in tissues with high energy demands such as heart, skeletal muscle, brown adipose tissue, liver, kidney and brain 1, 5 . Conversely, the expression level/ activity of PGC-1α and PGC-1α-dependent metabolic pathways are down-regulated in age and age-related diseases (muscle wasting, metabolic, neurodegenerative and neurodevelopmental disorders) 6, 7 , highlighting the key importance of this master homeostasis regulator in human physiology.…”