Browsing by Subject "DJ-1"

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    Cell model of DJ-1-associated Parkinson’s Disease
    (2017-10-31) Madison, Mackenzie; Hoang, Quyen; Wang, Mu; Hudmon, Andy
    Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of motor function resulting from dopaminergic neuronal death in the substantia nigra pars compacta leading to subsequent decreased striatal dopamine levels. The majority of PD cases are diagnosed as sporadic in nature, however 10% - 15% of patients show a positive family history of the disease. While many genes have been found to be implicated in the familial form of PD, early-onset autosomal recessive PD has been associated with mutations in PARK7, a gene which codes for the protein DJ-1. While there are many proposed roles of DJ-1 across numerous systems, the function of DJ-1 in relation to the development and progression of PD remains largely unclear. A first step towards determining this function is the creation of biologically relevant cell models of PD. The goal of this work was to design a representative cell model of DJ-1-associated PD in order to further study DJ-1 with the intention of elucidating its relevant function in relation of PD pathogenesis.
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    Discovery and Optimization of Inhibitors of the Parkinson’s Disease Associated Protein DJ-1
    (ACS, 2018-07) Tashiro, Shinya; Caaveiro, Jose M. M.; Nakakido, Makoto; Tanabe, Aki; Nagatoishi, Satoru; Tamura, Yasushi; Matsuda, Noriyuki; Liu, Dali; Hoang, Quyen Q.; Tsumoto, Kouhei; Biochemistry and Molecular Biology, School of Medicine
    DJ-1 is a Parkinson’s disease associated protein endowed with enzymatic, redox sensing, regulatory, chaperoning, and neuroprotective activities. Although DJ-1 has been vigorously studied for the past decade and a half, its exact role in the progression of the disease remains uncertain. In addition, little is known about the spatiotemporal regulation of DJ-1, or the biochemical basis explaining its numerous biological functions. Progress has been hampered by the lack of inhibitors with precisely known mechanisms of action. Herein, we have employed biophysical methodologies and X-ray crystallography to identify and to optimize a family of compounds inactivating the critical Cys106 residue of human DJ-1. We demonstrate these compounds are potent inhibitors of various activities of DJ-1 in vitro and in cell-based assays. This study reports a new family of DJ-1 inhibitors with a defined mechanism of action, and contributes toward the understanding of the biological function of DJ-1.