Evidence for a common biological pathway linking three Parkinson's disease‐causing genes: parkin, PINK1 and DJ‐1

Abstract

Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early-onset cases of PD are predominantly caused by mutations in the parkin, PINK1 and DJ-1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ-1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. DJ-1 is able to rescue the phenotype of PINK1-knockout Drosophila models, but not of parkin-knockouts, suggesting that DJ-1 may act in a parallel pathway to that of the PINK1/parkin pathway. To further elucidate a commonality between these three proteins, bioinformatics analysis established that Miro (RHOT1) interacts with parkin and PINK1, and HSPA4 interacts with all three proteins. Furthermore, 30 transcription factors were found to be common amongst all three proteins, with many of them being involved in transcriptional regulation. Interestingly, expression of these proteins and their associated transcription factors are found to be significantly down-regulated in PD patients compared to healthy controls. In summary, this review provides insight into common pathways linking three PD-causing genes and highlights some key questions, the answers to which may provide critical insight into the disease process.

Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome

“…Therefore loss of this protective thiol may render the cells more susceptible to oxidative insults. Second, mutations in DJ-1 and two other proteins, PINK1 and parkin, are responsible for the majority of cases of autosomal recessive, earlyonset Parkinson disease, a neurodegenerative disorder that produces progressive loss of dopaminergic neurons in the substantia nigra (44). Finally, we identified Cys 106 of DJ-1 as one of the succinated sites in adipocytes grown in high glucose/high insulin media (45).…”

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats

“…Most HSPs act as chaperones and imperfections in their function can lead to an accumulation of misfolded proteins (Patterson, 2006). HSPA4 has interaction with PD-causing genes, including parkin, DJ-1 and PINK1, although the role of HSPA4 in PD progression and pathogenesis is unclear (van der Merwe et al, 2015). The official full name of Hcrtr1 is hypocretin receptor 1.…”

A homozygous parkin p.G284R mutation in a Chinese family with autosomal recessive juvenile parkinsonism

“…Furthermore, accumulating evidence shows that parkin may share a common biological pathway with the PTEN-induced kinase 1 gene (PINK1) and DJ-1, the other two genes responsible for autosomal recessive PD, being involved in mitophagy, mitochondrial fusion and fission, mitochondrial trafficking. Loss of function of any of the three gene products may cause nigral degeneration, a pathological hallmark of PD [25,26].…”