Seminar Details
Speaker: Dr. Y. Hwan Kim, Professor of Allied Health Sciences & Director of Neuroscience Program at Boise State University
Host: Dr. Allan Albig, Biological Sciences
Title: Inhibition of deSUMOylation and cellular senescence as potential therapeutic targets for Parkinson’s disease.
Abstract: Parkinson’s disease (PD) is the most common neurodegenerative motor disease, which is primarily characterized by dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) in the midbrain and the formation of intraneuronal inclusions called “Lewy bodies” which contain alpha-synuclein as their major protein component. In my lab, we focus on targeting senescent astrocytes/microglia for therapeutic intervention in PD pathology. Particularly a cellular senescence marker, p21 was enhanced in alpha-synuclein preformed fibrils (PFF) injected in vitro, ex vivo and mouse brains. Our results suggested that PFF-induced pathology could lead to senescent astrocyte/microglia in mouse brains, which was validated in human PD patients SNpc (Verma et al., 2021). As a follow-up study, we found that the removal of senescent glia using senolytic (ABT-263) revealed a great potential as a novel therapeutic application in PFF-injected mouse brains to prevent neuronal loss in PD models. For the second project, we have been working on regulating small ubiquitin-like modifier (SUMO) as a therapeutic application for PD for the past 8 years. Our recent results and publications demonstrated that MPTP- or PFF-induced toxicity reduced the levels of SUMO1 on a-synuclein in the striatum and ventral midbrain, which were associated with high levels of Reactive Oxygen Species (ROS) and protein aggregation in brains, while Ubc9 overexpression-mediated SUMOylation protected the dopaminergic neurons in the striatum and Substantia Nigra against the toxicities (Verma et al., eNeuro, 2020). Interestingly, we found that the level of SUMO removing enzyme, SENP1 in human PD patient brains was higher than that in age-matched controls. We have investigated numerous SENP1 inhibitors including Momordin lc and found that the SENP1 inhibition protected dopaminergic neurons in the striatum and SNc in PFF-injected mice. This approach has provided insights into the role of SUMOylation in protecting dopaminergic neurons from protein aggregation or oxidative stress-mediated damages, suggesting SENP1 inhibition as a novel therapeutic application for PD and possibly other neurodegenerative diseases.
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