Jeff Bronstein, M.D., Ph.D
University of California, Los Angeles
Jeff Bronstein received his bachelor’s degree from the University of California, Berkeley and M.D. and Ph.D. from UCLA as a recipient of the Medical Scientist Training Program Award. He completed a residency in Neurology and fellowship training in Movement Disorders at UCLA and at Queens Square in London. Dr. Bronstein also completed a postdoctoral fellowship in molecular biology before being appointed an Assistant Professor of Neurology in 1994, Director of the Movement Disorders Program at UCLA in 1996. Professor of Neurology in 2006, and Professor of Molecular Toxicology in 2007. His clinical interests include the management of Parkinson’s disease (PD) and other movement disorders, surgical treatment of PD, and developing new therapies for patients. Dr. Bronstein’s research interests include the study of the causes of PD (environmental and genetic) using cell and zebrafish models as well as population-based studies. His research is supported by the NIH, Veteran Administration, and private foundations. Dr. Bronstein is the Principle Investigator of one of 6 National Parkinson’s Disease Centers (PADRECC) at the Veterans Administration Medical Center.
CLR01 and Parkinson’s disease
CLR01 was then tested in two novel zebrafish models of Parkinson’s pathology. In one of our models, human α-synuclein was overexpressed in neurons, which led to neuronal death and poor survival of the fish. CLR01 markedly attenuated α-synuclein toxicity (Figure 2) (Prabhudesai et al., Neurotherapeutics, 2012).
In a second model, we tested CLR01’s ability to protect against pesticide-induced toxicity (Lulla et al. Environ Health Perpect. 2016). Exposure to pesticides is known to be associated with an increased risk of developing PD and we recently found that chronic exposure to the fungicide Ziram is associated with a 3-fold increased risk of developing PD. Additional studies revealed that ziram and other pesticides in this class inhibit the ubiquitin proteasome system (UPS) resulting in increased α-synuclein in dopaminergic cells. Zebrafish embryos exposed to low concentrations of ziram (50 nM) showed abnormal swimming and a significant loss of dopaminergic neurons. This dopaminergic toxicity was markedly attenuated when we knocked down zebrafish synuclein with morpholinos suggesting that ziram-induced toxicity was at least partially synuclein-dependent. Treatment of the zebrafish with CLR01 also dramatically reduced ziram-induced dopaminergic neuron toxicity, showing that inhibiting the self-association of synuclein into toxic aggregates was sufficient to prevent its toxicity.