Journal Article

Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage

Jue Chen, Lian Li and Lih-Shen Chin

in Human Molecular Genetics

Volume 19, issue 12, pages 2395-2408
Published in print June 2010 | ISSN: 0964-6906
Published online March 2010 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/ddq113
Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage

Show Summary Details

Preview

Mutations in DJ-1 cause recessively transmitted early-onset Parkinson disease (PD), and oxidative damage to DJ-1 has been associated with the pathogenesis of late-onset sporadic PD. The precise biochemical function of DJ-1 remains elusive. Here, we report that DJ-1 is synthesized as a latent protease zymogen with low-intrinsic proteolytic activity. DJ-1 protease zymogen is activated by the removal of a 15-amino acid peptide at its C terminus. The activated DJ-1 functions as a cysteine protease with Cys-106 and His-126 as the catalytic diad. We show that endogenous DJ-1 in dopaminergic cells undergoes C-terminal cleavage in response to mild oxidative stress, suggesting that DJ-1 protease activation occurs in a redox-dependent manner. Moreover, we find that the C-terminally cleaved form of DJ-1 with activated protease function exhibits enhanced cytoprotective action against oxidative stress-induced apoptosis. The cytoprotective action of DJ-1 is abolished by the C106A and H126A mutations. Our findings support a role for DJ-1 protease in cellular defense against oxidative stress and have important implications for understanding and treating PD.

Journal Article.  7264 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.