Absence of nigral degeneration in aged parkin/DJ‐1/PINK1 triple knockout mice

Kitada, Tohru; Tong, Yiwei; Gautier, Camille; Shen, Jie

doi:10.1111/j.1471-4159.2009.06350.x

Cited by 225 publications

(183 citation statements)

References 44 publications

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“…Although VMAT2 activity was not examined in patients with DJ-1 mutation-derived Parkinson's disease, it would be interesting to do so. Contrary to human cases of familial forms of Parkinson's disease caused by mutations of parkin, pink1 and DJ-1 genes, corresponding knockout mice, even triple knockout mice, do not show obvious phenotypes of Parkinson's disease [32]. There are no significant differences in TH, DDC and VMAT2 levels between wild-type and DJ-1-knockout mice [33].…”

Section: Discussionmentioning

confidence: 89%

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

Ishikawa

Tanaka

Takahashi-Niki

et al. 2012

Biochemical and Biophysical Research Communications

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Loss-of-functional mutation in the DJ-1 gene causes a subset of familial Parkinson's disease. The mechanism underlying DJ-1-related selective vulnerability in the dopaminergic pathway is, however, not known. Dopamine is synthesized by two enzymes and then packed into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2). In this study, we found that knockdown of DJ-1 expression reduced the levels of mRNA and protein of VMAT2, resulting in reduced VMAT2 activity. Co-immunoprecipitation and pull-down experiments revealed that DJ-1 directly bound to VMAT2, and DJ-1 was co-localized with VMAT2 in cells. Furthermore, ectopic expression of wild-type DJ-1, but not that of L166P, M26I and C106S mutants of DJ-1, increased mRNA and protein levels of VMAT2 and VMAT2 activity. Since VMAT2 and a portion of DJ-1 are localized in the synaptic membrane, these results suggest that DJ-1, but not pathogenically mutated DJ-1, stimulates VMAT2 activity in the synapse by transactivation of the VMAT gene and by direct binding to VMAT2 and that cysteine 106 is necessary for the stimulating activity of DJ-1 toward VMAT2.

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Section: Discussionmentioning

confidence: 89%

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

Ishikawa

Tanaka

Takahashi-Niki

et al. 2012

Biochemical and Biophysical Research Communications

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“…This may be due to compensation resulting from long-term pink1/parkin loss. Indeed, pink1/parkin KO animals do not show dopaminergic loss (40,41). Importantly, however, the protection observed in WT cultures with BAG2 expression is abolished with either parkin or pink1 deficiency (Fig.…”

Section: Bag2 Regulates Parkin Translocation To Mitochondria In a Pink1mentioning

confidence: 82%

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Hage

Don-Carolis

et al. 2015

Journal of Biological Chemistry

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Emerging evidence has demonstrated a growing genetic component in Parkinson disease (PD). For instance, loss-of-function mutations in PINK1 or PARKIN can cause autosomal recessive PD. Recently, PINK1 and PARKIN have been implicated in the same signaling pathway to regulate mitochondrial clearance through recruitment of PARKIN by stabilization of PINK1 on the outer membrane of depolarized mitochondria. The precise mechanisms that govern this process remain enigmatic. In this study, we identify Bcl2-associated athanogene 2 (BAG2) as a factor that promotes mitophagy. BAG2 inhibits PINK1 degradation by blocking the ubiquitination pathway. Stabilization of PINK1 by BAG2 triggers PARKIN-mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD. Collectively, our findings support the notion that BAG2 is an upstream regulator of the PINK1/PARKIN signaling pathway. Parkinson disease (PD)2 is the second most common neurodegenerative disorder, characterized by selective loss of the pigmented dopaminergic neurons of the substantia nigra pars compacta (1). Although most PD cases are sporadic in nature (2), mutations in several genes have been linked to familial forms of PD (reviewed in Ref.3). Indeed, these familial genes serve as important vehicles to study the potential mechanisms of pathogenesis in PD. In this regard, increasing evidence suggests that mitochondrial dysfunction may play a critical role in both the inherited and sporadic forms of PD, although the precise role of mitochondrial dysfunction in PD is unclear (4). Recently, two familial recessive PD genes, PTEN-induced putative kinase 1 (PINK1), a mitochondrially localized serine/threonine kinase gene, and PARKIN, an E3 ubiquitin ligase gene, have been identified as acting along similar pathways in regulating mitochondrial quality control in mammalian systems (5-8). These findings are supported by genetic studies in Drosophila models of PD that show that PARKIN and PINK1 function in a common pathway, with PARKIN being a downstream player of PINK1 (9 -11). A third recessive PD gene, DJ-1, associated with the regulation of oxidative stress, also regulates PINK1/PARKIN-mediated control of mitochondrial health (12).PINK1 is normally shuttled to the inner mitochondrial membrane where it is processed by multiple proteases (13). The endogenous role of PINK1 at this site is unknown. However, PINK1-deficient cells display altered calcium homeostasis at the mitochondria as well as altered mitochondrial function (14). Processed PINK1 at the inner mitochondrial membrane has also been proposed to be shuttled to the cytosol, where it is degraded by the proteasome (15). However, under conditions of mitochondrial stress such as treatment with the mitochondrial uncoupler carbonyl cyanide p-chlorophenylhydrazone (CCCP) or with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP ϩ ), PINK1 can also regulate mitophagy in a PARKIN-dependent fashion (12, 16 -19). The framework by which this mitochondrial ...

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“…Furthermore, other studies have shown that Parkin also mediates proteasome-dependent degradation of outer membrane proteins of depolarized mitochondria, although it is controversial whether this process is required for mitophagy [60][61][62], these findings suggest that an autophagic defect may not be the only factor contributing to the pathogenesis of PINK1/Parkin-related Parkinson's disease. It would also be important to know whether PINK1/Parkin-mediated mitophagy occurs under physiological conditions, because most previous studies were performed in cells overexpressing Parkin, and PINK1/Parkin knockout mice failed to faithfully recapitulate Parkinson's disease in humans [63][64][65].…”

Section: Parkinson's Diseasementioning

confidence: 99%

Autophagy and human diseases

2013

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Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related (Atg) genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized.

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Absence of nigral degeneration in aged parkin/DJ‐1/PINK1 triple knockout mice

Cited by 225 publications

References 44 publications

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

Autophagy and human diseases

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