Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease

Abstract

Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP(+))-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP(+)-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.

Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila

“…Functional studies suggest that wildtype PINK1 may have a neuroprotective role (4) that is abrogated by pathogenic mutations in the PINK1 gene. Consistent with the notion, we have recently shown that PINK1 and DJ-1 physically associate and collaborate to protect cells against oxidative stress (15). These results suggest a potential role of PINK1 in maintaining mitochondrial homeostasis and in defending against oxidative stress.…”

“…In vitro, parkin and DJ-1 have been shown to protect cells from oxidative stress (26)(27)(28)(29)(30)(31). Moreover, PINK1 interacts with DJ-1 and digenic mutations of PINK1 and DJ-1 are associated in early onset familial form of PD (15). Consistent with our findings that antioxidants can ameliorate the dPINK1-dependent PD pathology in Drosophila are two recent reports that show that deletion mutants of dPINK1 result in abnormally functioning mitochondria, sensitization to oxidative stress, and mild degeneration of DA neurons (32,33).…”

Myostatin inactivation induces a similar muscle molecular signature in double-muscled cattle as in mice

“…14-3-3E is a member of the 14-3-3 family of phosphoserine-binding adapter molecules that mediate a general survival-promoting function through interaction with target proteins, by enhancing pro-survival signalling while suppressing activity of proapoptotic proteins (Porter et al, 2006). PINK1 encodes a Ser/ Thr kinase with a mitochondrial-targeting signal, and acts with DJ-1 to protect cells against oxidative stress-induced cell death (Tang et al, 2006).…”

Antioxidants put Parkinson flies back in the PINK

“…Consistent with this notion, a recent study reports that digenic mutations of PINK1 and DJ-1 are associated with early-onset familial PD cases (10). In addition, expression of these two pathogenic proteins potentiates susceptibility of SH-SY5Y cells to oxidative stress, and PINK1 and DJ-1 can form a complex when coexpressed in mammalian cells (10). PINK1 and DJ-1 appear to function in the same pathway as Parkin, which encodes an E3 ubiquitin ligase that is thought to function primarily in the cytoplasm, presumably to target specific protein targets for degradation or modified function͞local-ization (11).…”

“…PINK1 is likely to function in conjunction with another mitochondrial protein known as DJ-1 because mutations in this gene also cause autosomal recessive forms of PD. Consistent with this notion, a recent study reports that digenic mutations of PINK1 and DJ-1 are associated with early-onset familial PD cases (10). In addition, expression of these two pathogenic proteins potentiates susceptibility of SH-SY5Y cells to oxidative stress, and PINK1 and DJ-1 can form a complex when coexpressed in mammalian cells (10).…”