Mutations in the DJ-1 gene have been associated with autosomal recessive PD in 2003 (Bonifati et al. 2003). 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 is associated with autosomal recessive PD (review in Bonifati et al. 2004). The clinical phenotype is similar to that of parkin-related PD; however, DJ-1 mutations account for only 1%-2% of early-onset cases (Hedrich et al. 2004).
The DJ-1 gene was first cloned in 1997 in the course of a yeast two-hybrid screen for proteins interacting with c-myc (Nagakubo et al. 1997). It encodes a 189 amino acid protein, which is highly expressed in the testes, but can also be found in various tissues, including the brain (Bandopadhyay et al. 2004). The crystal structure of DJ-1 revealed that DJ-1 exists as a dimer (Honbou et al. 2003; Tao and Tong 2003; Wilson et al. 2003). Several functions have been ascribed to DJ-1. It restores the transcriptional activity of the androgen receptor (AR) following repression by PIASxa (protein inhibitor of activated STAT), which acts as a SUMO-1 (small ubiquitin-like modifier-1) ligase (Takahashi et al. 2001). DJ-1 can also positively regulate the AR-mediated transcriptional activity by binding to DJBP (DJ-1 binding protein), which seems to inhibit the AR by recruiting a histone deacetylase complex (Niki et al. 2003). Furthermore, DJ-1 was identified as the regulatory subunit of a RNA-binding protein complex (Hod et al. 1999). DJ-1 is converted into a pI variant in response to oxidative stress, suggesting a function as stress sensor (Mitsumoto et al. 2001). Based on this observation, it has been speculated that DJ-1 is linked to neurodegeneration via a role in the stress response. Structural similarities to the stress-inducible Escherichia coli chaperone Hsp31 led to the finding that DJ-1 has a chaperone-like activity; in vitro it prevents the heat-induced aggregation of luciferase or citrate synthase (Lee et al. 2003; Shendelman et al. 2004). Notably, this activity is maintained after oxidative stress and is not affected by ATP or ADP. In a cell culture model, it has been observed that downregulation of DJ-1 by siRNA enhances cell death induced by oxidative stress (Martinat et al. 2004; Taira et al. 2004; Yokota et al. 2003).
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