Chapter 3 - The DJ-1 gene and protein: links with Parkinson's disease

Abstract

Parkinson's disease (PD) was initially thought to be a solely sporadic disorder; however, many PD-associated genes have been identified with mutations that increase the likelihood of disease. PARK7 is one of these genes. Mutant alleles of PARK7 that result in loss of function of the encoded protein DJ-1 have been reported to cause early-onset, familial Parkinson's disease. DJ-1 is thought to be involved in many cellular pathways in multiple biochemical capacities as a chaperone, antioxidant, transcriptional regulator, deglycase, and protease. Despite extensive work supporting these roles, the mechanisms by which mutant DJ-1 causes PD remain unclear. Loss of DJ-1 function has been reported to cause elevated levels of reactive oxygen species and increased aggregation of other Parkinson's associated proteins, ultimately leading to neurodegeneration. DJ-1 overoxidation reportedly results in loss of function and increased buildup of nonfunctional protein within cells. Most studies report that wild-type DJ-1 in unstressed cells is located in the cytoplasm, but its location under conditions of oxidative stress is more controversial; localization in the cytoplasm, mitochondria, and nucleus has been reported. It has also been suggested that mutant, but not wild-type DJ-1 can localize to the mitochondria, leaving lower levels of the protein in the cytoplasm and other subcellular locations that may result in cytopathology.