Abstract Details

Title Discovering and Rescuing Toxic Autophagy Derangements in CMT4B3 Using a Novel iPSC-derived Peripheral Nervous System Model of MTMR5 Biology

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S5 - ALS and CMT: New Therapeutic Approaches (5:18 PM-5:30 PM)

Poster/Presentation
Number 010

Background

CMT4B3 is a rare, hereditary, incurable, and devastating neurologic disorder with heterogeneous manifestations, ranging from PNS involvement with sensory loss, muscle atrophy, foot deformities, and gait instability, to central nervous system (CNS) involvement with cognitive impairment, microcephaly, and multiple cranial neuropathies. CMT4B3 is caused by loss-of-function (LOF) mutations in the SBF1 gene, encoding the pseudophosphatase, MTMR5. MTMR5 participates in the metabolism of phosphoinositides that serve as membranal scaffolds for recruiting protein complexes overseeing induction of autophagy. Although the native function of MTMR5 has been identified, the precise mechanisms by which MTMR5 exerts contrasting functions and modifies cellular health in different cell and tissue types, thereby leading to the protean and cell type-specific manifestations of CMT4B3, are poorly understood. Previously established models of CMT4B3 consist of non-PNS cells and rodents but incompletely recapitulate the full spectrum of disease phenotypes found in humans.

Objective

To fully elucidate the pathophysiology of Charcot-Marie-Tooth disease type 4B3 (CMT4B3) and targetable mechanisms for therapy development, we have engineered a new human peripheral nervous system (PNS) cell model of CMT4B3.

Design/Methods We generated isogenic motor neurons and skeletal muscle (iMotor Neurons, iMuscle) from patient-derived iPSCs, and assessed markers of autophagy, cell viability, and treated cells with pharmacologic modulators of autophagy.

Results In CMT4B3 cells, there is marked attenuation of MTMR5 expression, heightened autophagic flux, and lower cell viability that is partially rescued by pharmacologic inhibition of autophagy. These phenotypes are more severe in iMotor Neurons compared to iMuscle, pointing to cell type-specific vulnerability to, and cell autonomous toxic effects of, LOF in MTMR5.

Conclusions

Our results confirm the biologic fidelity of our novel human PNS cellular system for modeling CMT4B3, and the foundational insights provided by our experimental platform will be invaluable for ongoing mechanistic investigations of MTMR5-related pathophysiology and discovering therapies for CMT4B3 and neurological disorders marked by dysregulated autophagy.

Authors/Disclosures
Jason Chua, MD, PhD (Johns Hopkins University) PRESENTER	Dr. Chua has nothing to disclose.
Sarah Stumpf	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.