Abstract Details

Title Rescuing Alpha-synuclein Toxicity Through Neuron-specific Enhancement of Autophagy

Topic Movement Disorders

Presentation(s) P7 - Poster Session 7 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-003

Objective To overcome proteostatic barriers and ameliorate Parkinson disease (PD) pathogenesis, we sought to determine whether knockdown of MTMR5 facilitates alpha-synuclein (asyn) turnover and rescues asyn proteotoxicity.

Background PD is a neurodegenerative movement disorder marked by progressive motor and non-motor symptoms that lead to profound disability. Neurodegeneration in PD relates to toxic aggregation of asyn, and mounting evidence shows that asyn can be degraded through the conserved pathway of autophagy. However, multiple aspects of autophagy are impaired in PD, and available methods to modulate autophagy fail to confer clinical benefits in patients because of the intrinsic resistance of neurons to these methods. This resistance stems in part from MTMR5 (myotubularin-related phosphatase 5), a potent autophagy regulator that we previously identified to be selectively enriched in neurons. MTMR5 acts as an autophagy suppressor, and MTMR5 knockdown enhances degradation of multiple autophagy substrates.

Design/Methods To investigate how and to what extent MTMR5 manipulation modifies asyn degradation and cell viability, we established a novel human induced pluripotent stem cell (iPSC)-derived neuron model of PD expressing fluorescently labeled autophagy effectors and asyn. Our PD model combined with super-resolution microscopy enables high-content, non-invasive optical monitoring of asyn degradation by autophagy in human neurons.

Results We found that knockdown of MTMR5 significantly augmented autophagic clearance of not only WT asyn, but also mutant variants of asyn associated with familial PD and that demonstrate enhanced aggregation. We also found that MTMR5 knockdown and pharmacologic stimulation of autophagy mitigated asyn-related neuronal death. We will next employ unbiased, genome-wide CRISPR-based screens to uncover key factors regulating MTMR5 in neurons.

Conclusions

Collectively, our findings attest to the neuroprotective effects of targeting MTMR5 for restoring asyn proteostasis. These studies also establish a novel research platform leveraging neuronal autophagy and myotubularin biology to discover innovative mechanisms for therapy development in PD and related neurodegenerative disorders.

Authors/Disclosures
Jason Chua, MD, PhD (Johns Hopkins University) PRESENTER	Dr. Chua has nothing to disclose.
Sami Barmada, MD (University of Michigan Department of Neurology)	Dr. Barmada has nothing to disclose.
Lois Weisman (University of Michigan)	No disclosure on file
Valina Dawson, PhD (Johns Hopkins University)	Dr. Dawson has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Valted Seq Inc. An immediate family member of Dr. Dawson has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Valted Seq Inc. Dr. Dawson has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for eNeuro. Dr. Dawson has stock in Valted Seq Inc. An immediate family member of Dr. Dawson has stock in Valted Seq Inc. Dr. Dawson has stock in D&D Pharmatech. An immediate family member of Dr. Dawson has stock in D&D Pharmatech. Dr. Dawson has stock in Inhibikase Therapeutics, Inc. An immediate family member of Dr. Dawson has stock in Inhibikase Therapeutics, Inc,. An immediate family member of Dr. Dawson has stock in American Gene Technologies International. An immediate family member of Dr. Dawson has stock in Abbvie. The institution of an immediate family member of Dr. Dawson has received research support from Sun Pharmaceutical Industries Ltd. The institution of an immediate family member of Dr. Dawson has received research support from Sebum. Dr. Dawson has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Dawson has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Dawson has received personal compensation in the range of $100,000-$499,999 for serving as a Advisor with Mitokini.
Ted M. Dawson, MD, PhD, FAAN (Institute for Cell Engineering, Johns Hopkins University School of Medicine)	Dr. Dawson has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Valted Seq Inc. An immediate family member of Dr. Dawson has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Valted Seq Inc. An immediate family member of Dr. Dawson has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for eNeuro. Dr. Dawson has stock in Valted Seq. Dr. Dawson has stock in American Gene Technologies International Inc. Dr. Dawson has stock in Inhibikase Therapeutics, Inc. Dr. Dawson has stock in D&D Pharmatech. Dr. Dawson has stock in Abbvie. An immediate family member of Dr. Dawson has stock in Valted Seq Inc. An immediate family member of Dr. Dawson has stock in Inhibikase Therapeutics. An immediate family member of Dr. Dawson has stock in D&D Pharmatech. The institution of Dr. Dawson has received research support from Sun Pharmaceutical Industries Ltd. The institution of Dr. Dawson has received research support from Aevum. Dr. Dawson has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Dawson has received intellectual property interests from a discovery or technology relating to health care. Dr. Dawson has received personal compensation in the range of $100,000-$499,999 for serving as a Advisor with Mitokinin.

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