Whenever a new gene for a major neurodegenerative disease is uncovered, it creates a blast of excitement and a flurry of lab activity. This paper is likely to have that effect, as it describes a new gene for autosomal recessive early-onset Parkinsonism with a potentially very interesting biology. Bonifati and coworkers performed homozygosity mapping of a chromosome 1 locus associated with early-onset Parkinsonism in two families from Holland and Italy. After reducing the critical region to 5.6 Mb, they screened for expression of known genes in the region by RT-PCR and found that a candidate gene, DJ-1, could not be amplified from one of the Dutch patients. They subsequently demonstrated that the Dutch family harbors a 14 kb deletion in DJ-1, which results in loss of expression. Analysis of DJ-1 cDNA from the Italian family revealed a homozygous point mutation in a highly conserved residue (L166). These mutations were absent from 720 chromosomes analyzed from the general Dutch and Italian populations, but cosegregated precisely with affected members of the two families. Structural...  Read more

Whenever a new gene for a major neurodegenerative disease is uncovered, it creates a blast of excitement and a flurry of lab activity. This paper is likely to have that effect, as it describes a new gene for autosomal recessive early-onset Parkinsonism with a potentially very interesting biology. Bonifati and coworkers performed homozygosity mapping of a chromosome 1 locus associated with early-onset Parkinsonism in two families from Holland and Italy. After reducing the critical region to 5.6 Mb, they screened for expression of known genes in the region by RT-PCR and found that a candidate gene, DJ-1, could not be amplified from one of the Dutch patients. They subsequently demonstrated that the Dutch family harbors a 14 kb deletion in DJ-1, which results in loss of expression. Analysis of DJ-1 cDNA from the Italian family revealed a homozygous point mutation in a highly conserved residue (L166). These mutations were absent from 720 chromosomes analyzed from the general Dutch and Italian populations, but cosegregated precisely with affected members of the two families. Structural analysis of DJ-1 suggested that the point mutation, which substitutes a proline for a leucine, would likely disrupt a C-terminal alpha helix.

Little is known about the function of DJ-1, but intriguing clues exist. DJ-1 was previously shown to bind to PIAS proteins, a family of SUMO-1 ligases. Sumoylation is a post-translational modification analogous to ubiquitination that involves covalent attachment of a small protein, SUMO. SUMO is structurally similar to ubiquitin, and is reversibly conjugated to many different proteins. However, in contrast to ubiquitination, attachment of SUMO does not usually result in substrate degradation, but rather, results in altered regulation of substrate function, including activation of transcription factors and changes in subcellular localization. In this regard, COS cell transfection experiments in the present study showed that the DJ-1 point mutation altered its subcellular localization. Whereas wild-type DJ-1 was diffusely distributed in the cytoplasm and nucleus, L166P DJ-1 from the Italian family was concentrated in mitochondrial and nuclear compartments.

The association of DJ-1 with SUMO-1 ligases is interesting because the only other known gene identified in early-onset Parkinsonism, parkin, functions as an E3 ubiquitin ligase. Although it has been assumed that parkin loss-of-function mutations are pathogenic through effects on protein degradation, the ubiquitin pathway also regulates the activity of some transcription factors and signal transduction molecules independently of their degradation. Hence, it is possible that altered ubiquitination or sumoylation may induce neurodegeneration through dynamic effects on signal transduction, rather than protein degradation. In fact, there is no pathological evidence of defective protein degradation in early-onset autosomal recessive forms of Parkinsonism, as these cases typically lack Lewy bodies or other protein deposits.

The authors speculate that DJ-1 may participate in oxidative stress responses based on previous reports showing that DJ-1 may be modified by reactive oxygen species, and that a yeast DJ-1 homolog is induced by oxidative stress. These observations raise the possibility that DJ-1 may function to protect against oxidative stress, possibly through a stress response signal transduction pathway, and that DJ-1 loss-of-function mutations may make neurons more vulnerable to dopamine-related oxidative stress. It will now be important to confirm the association of DJ-1 with Parkinsonism in other families, and to obtain a greater understanding of the normal biology of this heretofore obscure protein.

View all comments by Bruce Yankner

This is potentially one of the most important findings in the Parkinson's disease field in recent years. What is particularly important is that the DJ-1 gene apparently encodes a protein involved in cellular resistance to oxidative stress, and that the authors’ data are consistent with a loss-of-function of DJ-1 as being responsible for the PARK7 inherited form of Parkinson's disease. If correct, this places oxidative stress as a PRIMARY cause of neuronal degeneration in Parkinson's rather than just a downstream consequence of more seminal upstream abnormalities. Of course, the findings also identify DJ-1 as a target for preventative and therapeutic intervention in Parkinson's disease. It will now be important to determine whether DJ-1 is also involved in the more common sporadic forms of Parkinson's disease and, of course, to produce animal models in which the defective DJ-1 gene is expressed in mice.

View all comments by Mark Mattson

Bonifati and colleagues bring genetic evidence of oxidative imbalance to the field of Parkinson’s disease research. In light of the abundant biochemical data demonstration nitration (Good et al., 1998; Giasson et al., 2002), lipid peroxidation and glycation (Castellani et al., 2002), and nucleic acid oxidation (Zhang et al., 1999), their data make a compelling case for a pivotal involvement of oxidative imbalance in Parkinson’s. Genetics brings together the oxidative stress response (DJ-1), proteolytic imbalance (parkin), and fibrillogenesis (synuclein) as critical factors in this disease. However, seen in the context of other neurodegenerative diseases, it repeats the same elements linking these pathogenetic entities. Understanding the role of DJ-1 in Parkinson’s disease should provide new insights for the treatment of Parkinson’s.

References:
Bonifati V, Rizzu P, van Baren MJ, et al. (2002) Mutations in the DJ-1 gene associated with autosomal recessive early onset Parkinsonism. Sciencexpress, 21 November 2002.

Castellani RJ, Perry G, Siedlak SL, Nunomura A, Shimohama S, Zhang J, Montine T, Sayre LM, Smith MA (2002) Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans. Neurosci Lett 319, 25-28.

Giasson BI, Ischiropoulos H, Lee VM-Y, Trojanowski JQ (2002) The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer's and Parkinson's diseases. Free Radic Biol Med 32, 1264-1275.

Good PF, Hsu A, Werner P, Perl DP, Olanow CW (1998) Protein nitration in Parkinson's disease. J Neuropathol Exp Neurol 57, 338-342.

Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG, Montine TJ (1999) Parkinson’s disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol 154, 1423-1429.

View all comments by George Perry
View all comments by Mark A. Smith

I think this is a wonderful discovery. It is going to open up new possibilities and opportunities for understanding the pathogenesis of PD.

View all comments by Ted Dawson

I fully agree with the previous comments. DJ-1 as the gene product of the PARK7 locus indeed provides us with the unique opportunity to readdress, in a comprehensive model, all of the previously observed pathogenetic aspects of Parkinson's disease. These Include, among others, abnormalities in the ubiquitin proteasomal pathway, dopamine metabolism-related oxidative stress, and mitochondrial dysfunction.

View all comments by Michael Schlossmacher