Crystallizing ideas about Parkinson's disease

Genetic forms of Parkinson's disease (PD) are useful in helping us to understand the underlying pathophysiology of this disorder in both its rare familial forms and the more common “sporadic” type. Three genes are unambiguously causal in different PD families: α-synuclein, parkin, and DJ-1 (reviewed in ref. 1). Two recessive mutations have been found in DJ-1, a large deletion and an L166P point mutation (2). DJ-1 mutations are likely to result in loss of protein function, and, hence, deciphering the normal cellular role of DJ-1 will be key to understanding how mutations cause disease.

DJ-1 has a number of functions, several of which may be relevant to the pathways that underlie PD (3). It was cloned independently in different laboratories examining processes as varied as cellular transformation, RNA binding, and male fertility (4–6). For this reason, and because DJ1 is a member of a large superfamily of proteins, we have to be cautious in assigning a PD-specific function. In this issue of PNAS, the report by Wilson et al. (7) of the detailed crystal structure of DJ-1 adds considerably to our understanding of what DJ-1 is and what it is not. Two additional studies showing DJ-1 at different resolutions are now in press (8, 9). All three structures show a similar overall folding pattern and demonstrate that DJ-1 is a dimer, which is confirmed in two of these papers by additional techniques. There are similarities to previously solved structures within the DJ-1 superfamily, namely the bacterial proteins PH1704 (10), a protease, and heat shock protein 31 (Hsp31) (7), a chaperone from Escherichia coli. Although the different proteins in the superfamily have a general pattern of folding that is similar (Fig. 1), there are also substantial differences. For example, PH1704 is a hexamer compared …