The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization

Abstract

Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1. WT or C53A DJ-1 was readily oxidized in cultured cells, generating a pI 5.8 isoform, but an artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was promoted by the crystallization procedure. In addition, oxidation-induced mitochondrial relocalization of DJ-1 and protection against cell death were abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against neuronal death, and that this is signaled by acidification of the key cysteine residue, C106.

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.…”

“…DJ-1 was first identified by our group as a novel oncogene product [1] and was later found to be a causative gene product of a familial form of PD, PARK7 [2]. DJ-1 plays roles in transcriptional regulation [3][4][5][6][7][8] and anti-oxidative stress reaction [9][10][11][12], and loss of its function is thought to affect the onset of PD. DJ-1 has three cysteines at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively).…”

“…DJ-1 has three cysteines at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively). Although oxidation of C106 is necessary for DJ-1 to exert its activity [11][12][13], further oxidation of C106 is thought to render DJ-1 inactive [14], and such oxidized DJ-1 has been observed in patients with the sporadic form of PD and Alzheimer disease [15,16].…”

“…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].…”

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

“…PARK7 is localized in the cytoplasm and the nucleus; it has also been shown that some PARK7 is localized in the mitochondria [9,10,19,20]. Several lines of evidence suggest that PARK7 is secreted from cells into the circulation despite the fact that PARK7 lacks a secretory signal sequence [21–29].…”