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ACCEPTED MANUSCRIPT phosphorylates a mitochondrial protein upon stress which can activate a pathway converging at parkin or at a target downstream parkin. Obviously, PINK1 is not essential for parkin function, and consequently, the functional interaction of PINK1 and parkin might not fit into a simple, linear pathway. In line with a more complex link between parkin and PINK1, parkin can prevent evoked mitochondrial cytochrome c release, while PINK1 can not [192]. Clearly, more studies are needed to unravel the role of parkin and PINK1 in mitochondrial protection, remodeling and clearance and the mechanism underlying their functional interaction. Three recent studies in Drosophila addressed the role of HtrA2/Omi as another possible player in the PINK1/parkin game. While the fly studies are in agreement on the functional interaction of PINK1 and parkin, this is strikingly different for the role of HtrA2/Omi. Using ectopic expression in the Drosophila eye, Whithworth et al. observed that HtrA2/Omi genetically acts downstream of PINK1, but functions independently of parkin. They also showed that rhomboid-7 (presenilin- associated rhomboid-like [PARL] in mammals) is required to cleave the precursor forms of both PINK1 and HtrA2/Omi [229]. However, Yun et al. reported that HtrA2/ Omi null mutants do not show defects in mitochondrial integrity [230]. In addition, ACCEPTED MANUSCRIPT they found no evidence for a genetic interaction between PINK1 and HtrA2/Omi in loss-of-function studies. Conversely, Tain et al. found mild mitochondrial defects in HtrA2/Omi null flies and observed that HtrA2/Omi can partially substitute for PINK1 loss of function [231]. PINK1/HtrA2/Omi double mutant flies showed a phenotype identical to that of PINK1 mutants, while the phenotype of parkin/HtrA2/Omi double mutants was stronger than that of either mutant alone, which led the authors to conclude that parkin and HtrA2/Omi are both downstream effectors of PINK1, but act in parallel pathways. 31
2.3. DJ-1 ACCEPTED MANUSCRIPT Mutations in the DJ-1 gene, encoding a 189 amino acid protein, have been associated with rare cases of early onset autosomal recessive PD [232]. A large deletion and a missense mutation (L166P) leading to the rapid degradation of the mutant protein were the first mutations identified in patients, indicating that a loss of DJ-1 function can cause parkinsonism (rev. in [233]). DJ-1 belongs to the ThiJ/PfpI family and shares structural similarities with the stress-inducible E. coli chaperone Hsp31 [234]. Various functions have been ascribed to DJ-1. Clearly, overexpression of DJ-1 protects neurons from oxidative stress-induced damage and DJ-1 deficiency renders cells more susceptible to oxidative injury [197, 235-242]. DJ-1 is converted into a more acidic pI variant in response to oxidative stress, due to the formation of cysteine-sulfinic acid at cysteine 106 [243-245]. Notably, cysteine 106 is essential for the neuroprotective activity of DJ-1 [237, 244, 246, 247]. Studies on the subcellular localization of DJ-1 reported the presence of DJ-1 in cytosolic, mitochondrial and nuclear compartments; mitochondrial localization of DJ-1 was enhanced by oxidative ACCEPTED MANUSCRIPT stress [248-250]. Substitution of cysteine 106 by alanine interfered with both mitochondrial localization and protection against mitochondrial toxins [244].Within mitochondria endogenous DJ-1 was found in the matrix and intermembrane space [251]. Junn et al. recently observed that endogenous DJ-1 translocates to mitochondria (within 3 hours) and the nucleus (within 12 hours) of human neuroblastoma cells in response to oxidative stress [252]. Interestingly, mitochondrial targeting of DJ-1 via fusion to a mitochondrial targeting signal sequence increased its neuroprotective acitivity. The authors of this study reported that the mutation of 32
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