Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locusSREBF1as a regulator of mitophagy

Abstract

Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, termed mitophagy. We undertook a genome-wide RNAi screen as an unbiased approach to identify genes regulating the PINK1/Parkin pathway. We identified several genes that have a conserved function in promoting mitochondrial translocation of Parkin and subsequent mitophagy, most notably sterol regulatory element binding transcription factor 1 (SREBF1), Fbox and WD40 domain protein 7 (FBXW7), and other components of the lipogenesis pathway. The relevance of mechanisms of autosomal recessive parkinsonism to sporadic PD has long been debated. However, with the recent identification of SREBF1 as a risk locus for sporadic PD, our findings suggest a common mechanistic link between autosomal recessive and sporadic PD, and underscore the importance of mitochondrial homeostasis. P arkinson disease (PD) is an age-related neurodegenerative disease caused principally by the loss of midbrain dopaminergic neurons, resulting in motor disturbances, such as postural instability, resting tremor, and bradykinesia, as well as other nonmotor symptoms. Current therapeutic strategies alleviate symptoms by the replacement of dopamine, with variable efficacy and substantial side effects. However, there are currently no established curative, preventative, or disease-modifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis. Genetic analyses have identified causative mutations for autosomal dominant and recessive forms of familial parkinsonism. Functional studies of these genes have provided great insight into potential pathogenic mechanisms of inherited forms of PD; however, it is unclear how these may relate to the more common sporadic forms of PD. To gain insight into the genetic influence in sporadic PD, genome-wide association studies (GWASs) have revealed several loci that are significantly associated with the occurrence of PD, and so are considered potential risk factors. However, we lack mechanistic insight into how many of the associated risk loci may contribute to pathogenesis.Mitochondrial dysfunction has long been considered a key contributing factor in the pathogenesis of PD, with evidence from postmortem tissue, epidemiological studies, and genetics. In particular, a body of evidence indicates that two genes linked to recessive parkinsonism, PTEN-induced kinase 1 (PINK1) and parkin, act in a common pathway to regulate mitochondrial turnover, providing an attractive hypothesis for the impact of mitochondrial homeostasis on pathogenesis (1). The process of mitophagy to degrade dysfunctional mitochondria has been extensively studied using uncoupling agents to dissipate the mitochondrial membrane potential (ΔΨm) (2). Following loss of ΔΨm, PINK1 accumulates on the outer mit...

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

“…Recently, in a whole genome RNAi screen that aimed to identify factors that promote mitophagy mediated by PARK2, the lipogenesis pathway was implicated with 4 genes of this pathway, SREBF1, SREBF2, FBXW7 and GSK3A, among the top hits. 29,167 Knockdown of SREBF1 blocks both the translocation of PARK2 to the mitochondria and the consequent mitophagy, an effect that is independent of PINK1 expression levels. 167 Therefore it is hypothesized that reduced SREBF1 expression my lead to reduced mitophagy and risk for PD.…”

“…29,167 Knockdown of SREBF1 blocks both the translocation of PARK2 to the mitochondria and the consequent mitophagy, an effect that is independent of PINK1 expression levels. 167 Therefore it is hypothesized that reduced SREBF1 expression my lead to reduced mitophagy and risk for PD.…”

Autophagosome dynamics in neurodegeneration at a glance

“…Depletion of DJ-1, another Parkinson's-disease-associated gene, disrupts both mitochondrial dynamics and morphology (Hao et al, 2010;Irrcher et al, 2010;Thomas et al, 2011). In addition, two other Parkinson's-diseaseassociated proteins, F-box domain-containing protein (Fbxo7; also known as PARK15) and sterol regulatory element binding transcription factor (SREBF1) are also implicated in mitophagy (Burchell et al, 2013;Ivatt et al, 2014).…”

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

“…In contrast, neurotoxin-triggered mitophagy does not require accumulation of PINK1 and Parkin on the mitochondria, although a possible role for ubiquitin ligases was not excluded (19). Steroid metabolism and ceramides may also play a role in PINK1-Parkin dependent and -independent mitophagy pathways (49,94).…”