The Role of PGC-1α in the Pathogenesis of Neurodegenerative Disorders

Abstract

Mitochondrial dysfunction is a common hallmark of ageing-related diseases involving neurodegeneration. Huntington's disease (HD) is one of the most common monogenetic forms of neurodegenerative disorders and shares many salient features with the major sporadic disease of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). Recent evidence from the study of transgenic and knockout animal models of HD has stimulated new perspectives on mitochondrial dysfunction in HD and possibly other neurodegenerative diseases. The transcriptional co-activator PGC-1α, originally described as a metabolic master regulator in peripheral tissues such as brown adipose tissue (BAT) and muscle, has emerged as a molecular link between transcriptional dysregulation and mitochondrial dysfunction in the brain. PGC-1α knockout mice display many phenotypic similarities to transgenic mouse models of HD and the gene-expression analysis of tissues from HD patients revealed a disruption of the PGC-1α regulatory pathway. Hence, mitochondrial and transcriptional dysregulation in HD - previously thought to be unrelated mechanisms of neurodegeneration - appear to be directly linked at the molecular level. The clinical and therapeutic potential of targeting the PGC-1α in HD is further highlighted by the finding that common genetic variations in the PGC-1α gene significantly modify the disease onset, delaying the onset of motor symptoms by several years. The present review provides an overview of the advances in the understanding of the role of the PGC-1α system in HD pathogenesis and explores the implications for ALS, AD and PD.

Non-motor Behavioral Alterations of PGC-1α-Deficient Mice – A Peculiar Phenotype With Slight Male Preponderance and No Apparent Progression

“…Despite the fact that PGC-1α-deficiency has been linked to various neurodegenerative disorders that are associated with psychic alterations (Rona-Voros and Weydt, 2010; Szalardy et al, 2015) and also with schizophrenia (Jiang et al, 2013; McMeekin et al, 2016) and the fact that a GWAS study has linked the chromosomal localization of the PGC-1α gene ( PPARGC1A , 4p15.1-2) to schizophrenia and bipolar disorder (Christoforou et al, 2007), only a few studies have addressed psychic behavioral alterations in the literature. In addition, these dealt only with specific aspects, such as anxiety-related behavior (Leone et al, 2005), depression-related behavior (Agudelo et al, 2014), and certain hippocampal functions (Lucas et al, 2014a; Bartley et al, 2015), and the analyses were performed in different PGC-1α knockout strains, evaluating either only males or females and males in a pooled manner ( Table 4 ).…”

“…In addition to its role in diseases related to fat and glucose metabolism (Wu et al, 2016), the deficient function of PGC-1α has been implicated in the pathogenesis of various CNS diseases, especially where defective mitochondrial function has been described as one of the key pathogenic factors, such as in HD, AD, PD, and MND (Rona-Voros and Weydt, 2010; Szalardy et al, 2015). Furthermore, increasing evidence indicate a potential role of PGC-1α in various psychiatric disorders, including schizophrenia (McMeekin et al, 2016) and depression (Agudelo et al, 2014).…”

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

“…Cumulative investigations have uncovered multiple HD-associated cell-autonomous impairments in striatal MSNs that are detrimental for these cells, including transcriptional deregulation, neuronal excitotoxicity, mitochondrial dysfunction, activation of proteases, protein aggregation and deregulation of intracellular trafficking (Bithell et al, 2009; Cha, 2007; Chen, 2011; Cowan et al, 2008; Graham et al, 2009; Leavitt et al, 2006; McGuire et al, 2006; Mehta et al, 2013; Metzler et al, 2007; Qin and Gu, 2004; Rona-Voros and Weydt, 2010; Rosenstock et al, 2010; Sun et al, 2001; Yuen et al, 2012). However, none of these putative pathogenic mechanisms adequately explains the selective profiles of cellular vulnerability in HD, the defining hallmark of all neurodegenerative diseases.…”

Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease

“…In essence, PGC1alpha is an important negative regulator of oxidative stress, mitochondrial dysfunction, lipotoxicity, and insulin resistance (177–179). The relevance of these data to AD is that genetic deficiencies in PGC1 alpha increase proneness to neurodegeneration (179, 180). This suggests that PGC1 alpha may represent an excellent therapeutic target for AD, and possibly other major neurodegenerative diseases as well.…”