DJ-1 Is a Redox-Dependent Molecular Chaperone That Inhibits α-Synuclein Aggregate Formation

Abstract

Parkinson's disease (PD) pathology is characterized by the degeneration of midbrain dopamine neurons (DNs) ultimately leading to a progressive movement disorder in patients. The etiology of DN loss in sporadic PD is unknown, although it is hypothesized that aberrant protein aggregation and cellular oxidative stress may promote DN degeneration. Homozygous mutations in DJ-1 were recently described in two families with autosomal recessive inherited PD (Bonifati et al. 2003). In a companion article (Martinat et al. 2004), we show that mutations in DJ-1 alter the cellular response to oxidative stress and proteasomal inhibition. Here we show that DJ-1 functions as a redox-sensitive molecular chaperone that is activated in an oxidative cytoplasmic environment. We further demonstrate that DJ-1 chaperone activity in vivo extends to α-synuclein, a protein implicated in PD pathogenesis.

DJ-1 binds to mitochondrial complex I and maintains its activity

“…While Zhang et al. reported that DJ-1 is located in the mitochondrial matrix and intermembrane space [24], Canet-Aviles et al reported that DJ-1 is located in the outer membrane but not inside of mitochondrial outer membrane [11]. Although the reasons for this discrepancy are not clear, different cells and methods used to identify the localization of DJ-1 might have given rise to the discrepancy.…”

“…These findings indicate that the function of mitochondrial complex I is related to the onset of PD. DJ-1 is located both in the cytoplasm and nucleus [1] and has recently been shown to be located in mitochondria [11,[24][25][26]. It has also been reported that some parts of DJ-1 were translocated into mitochondria after cells had been subjected to oxidative stress to protect cells from oxidative stress-induced cell death [27][28][29][30].…”

Tumours and tremors: how PTEN regulation underlies both

“…In both organisms, the increased susceptibility to oxidative stress can be rescued by activation of the PI3 0 K pathway (Kim et al, 2005b;Meulener et al, 2005;Yang et al, 2005). Other work has implicated DJ-1 as a sensor of reactive oxygen species and as a molecular chaperone (Shendelman et al, 2004), and DJ-1 may be able to influence the protein stability or oxidative state of elements of the PI3 0 K pathway. For example, PTEN and ASK1, a component of a DJ-1-containing complex (Junn et al, 2005), are both regulated by thioredoxin (Meuillet et al, 2004).…”

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…All impairments were reversed by restitution of DJ-1 expression. DJ-1 is normally activated by an oxidative cytoplasmic environment [278]. Shendelman and colleagues [278] described a role for DJ-1 as a redox-sensitive molecular chaperone, which was able to inhibit a-syn aggregate formation.…”

“…DJ-1 is normally activated by an oxidative cytoplasmic environment [278]. Shendelman and colleagues [278] described a role for DJ-1 as a redox-sensitive molecular chaperone, which was able to inhibit a-syn aggregate formation. Another study in DJ-1-deficient mice showed that the complex I inhibitor paraquat decreased proteasome activity concomitant with decreased ATP and regulatory subunit levels [279].…”