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

Parkinson’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. 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. The 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. While mutations in -synuclein (and UCH-L1) result in a rare autosomal dominant form of PD, mutations in DJ-1, like those of parkin, cause a clinically characteristic autosomal recessive juvenile onset form of PD (AR-JP). 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, mutations in DJ-1 have so far only been detected in two consanguineous European families. The DJ-1 gene contains 8 exons; exons 1 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 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. 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. 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. 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 such as, for example, protein structure, enzymatic activity or protein-protein interactions. In this issue, Abou-Sleiman and colleagues demonstrate the presence of DJ-1 mutations in a large cohort of early onset PD patients, but not in later onset sporadic PD patients. Using a direct sequencing approach of the entire DJ-1 ORF, they detected a single homozygous missense mutation in exon 2 (M26I) in an Ashkenazi Jewish patient, and a further heterozygous exon 7 mutation (D149A) in an Afro-Caribbean patient together with a homozygous silent mutation (G78G) which abolishes a predicted exonic splice enhancer site. A heterozygous R98Q mutation was also found in three pathologically proven cases of idiopathic PD. A heterozygous R98Q mutation was recently reported in three unrelated subjects and an A104T mutation was found as a heterozygous mutation in a sporadic PD patient. Two additional mutations, IVS61G3C and c.56delC c.57G3A that are predicted to disrupt the function of DJ-1 have been described. The c.56delC c.57G3A mutation is predicted to result in a truncated protein of 18 amino acids, followed by a premature stop. The IVS6-1G3C mutation results in a single nucleotide substitution in a conserved sequence of the invariant AG splice acceptor site of intron 6 and this variant is predicted to have drastic consequences on DJ-1 RNA and would lead to an aberrant transcript. These studies taken together indicate that DJ-1 mutations are a rare cause of hereditary PD, but mutations in DJ-1 are still the second most common known genetic cause of PD. Furthermore, mutations in DJ-1 seem to rarely contribute to the etiology of the sporadic form of the disease. At this juncture it is not clear whether the heterozygous mutations in DJ-1 (D149A, R98Q, and A104T) are disease-causing mutations. They could simply represent benign mutations, they might contribute to disease through interactions with as yet unidentified muEDITORIAL