Genetics of Parkinson's disease: What do mutations in DJ‐1 tell us?

Abstract

's disease (PD), the second most common progressive neurodegenerative disorder, is characterized pathologically by the selective loss of dopaminergic neurons from the substantia nigra pars compacta and the presence of intracytoplasmic proteinaceous inclusions termed Lewy bodies 1,2 . The etiology of PD remains unclear, and although PD occurs most commonly as a sporadic idiopathic form, the recent identification of genetic mutations in rare familial cases of PD has provided tremendous insight into the molecular pathogenesis of this neurological disease. So far, three genes have been clearly linked to PD; ␣-synuclein, parkin and more recently DJ-1. A mutation in a fourth gene, UCH-L1, has also been implicated. 2-5The recent discovery of deletions or mutations in the DJ-1 gene will undoubtedly provide new clues to the pathogenesis of PD and open up new exciting areas of PD research. 6 While mutations in ␣-synuclein (and UCH-L1) result in a rare autosomal dominant form of PD, 2-4 mutations in DJ-1, like those of parkin, cause a clinically characteristic autosomal recessive juvenile onset form of PD (AR-JP).6 Thus, such mutations are thought to lead to a loss of DJ-1 function. While parkin mutations appear to be the most common cause of AR-JP accounting for up to half of all cases, 7 mutations in DJ-1 have so far only been detected in two consanguineous European families. The DJ-1 gene contains 8 exons; exons 1 A/B are alternatively spliced and non-coding, while exons 2 to 7 comprise the open reading frame (ORF) encoding a 189 amino acid protein. In one Dutch family, a large homozygous genomic deletion encompassing exons 1 A/B to 5 of DJ-1 leads to an absence of gene product, while in an Italian family a homozygous point mutation results in the substitution of a highly conserved leucine for a proline at position 166 (L166P) of the DJ-1 protein. 6 The L166P mutation, centrally located within a carboxyl-terminal ␣-helix, is predicted to disrupt the tertiary structure of the DJ-1 protein. Indeed, the recent elucidation of the crystal structure of DJ-1 demonstrates that DJ-1 exists in a homodimeric form, whereas the L166P mutant form appears to exist only as a monomer. [8][9][10] Hence, the pathogenic L166P mutation appears to impair dimerization of DJ-1, which is probably critical for its function. Our results confirm that the L166P mutation disrupts dimerization of DJ-1 through destabilization of the protein (D.J.M., L. Zhang, T.M.D and V.L.D.). Furthermore, while DJ-1 exhibits a ubiquitous cellular localization pattern, the L166P mutation results in mislocalization of DJ-1 to mitochondria. 6 Thus, in light of the fact that the functional role of DJ-1 remains elusive, investigating the effects of such mutations on the basic properties of DJ-1 can provide novel insights into how loss of DJ-1 function might lead to neurodegeneration. However, the elucidation of additional disease-causing DJ-1 mutations in AR-JP or sporadic PD patients will help to determine which critical properties of DJ-1 function are affected in PD suc...

Animal Models of Parkinson's Disease: Vertebrate Genetics

“…The results collectively emphasize DJ-1's role as a redox-sensitive molecular chaperone that provides protection against cellular stresses (Moore et al 2003). DJ-1 seems to function as an atypical peroxiredoxin-like p (Andres-Mateos et al 2007).…”

DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death

“…Mutations in the DJ-1 gene have been associated with autosomal recessive early onset PD; a homozygous genomic deletion encompassing exon 1-5, a homozygous L166P missense mutation and other homozygous and heterozygous mutations of DJ-1 have been identified in patients with familial or sporadic PD. [5][6][7][8][9] The crystal structure and yeast two-hybrid data indicate that DJ-1 exists as homodimer harboring domains found in both heat shock protein chaperones and ThiJ/PfpI proteases. [10][11][12] By way of contrast, the L166P mutant exists as a monomer, because it destabilizes the dimer interface.…”

Genetic Models of Parkinson’s Disease

“…DJ-1 belongs to the DJ-1/ThiJ/Pfpl protein superfamily of molecular chaperones. The single-domain, DJ-1 protein exists as a homodimer localized in the nucleus, cytosol, and the intermembrane space of the mitochondria [3,129,130,[136][137][138][139]. The single-domain, DJ-1 protein exists as a homodimer localized in the nucleus, cytosol, and the intermembrane space of the mitochondria [3,129,130,[136][137][138][139].…”

“…The first two mutations identified in the DJ-1 gene were noted in Dutch and Italian families in which a large genomic deletion resulted in a 14 kb deletion of the gene's promoter region as well as exons 1-5, and a homozygous missense mutation (L166P), leading to loss of DJ-1 stability, localization, and expression [129,130,134,136,139]. Introduction of the L166P mutation in model systems results in a protein that is unable to homodimerize and is quickly subject to proteasomal degradation [130,134].…”

“…Introduction of the L166P mutation in model systems results in a protein that is unable to homodimerize and is quickly subject to proteasomal degradation [130,134]. Since the identification of the initial mutations, several others have been noted, including a M26I mutation and D194A and A104T mutations [130,136]. The precise effect of these mutations on neuronal survival, however, remains to be elucidated [130,136].…”