Abstract Details

Title New Roles for GARS1 in Organelle Dynamics and Misregulation in the Peripheral Neuropathy Charcot Marie Tooth Disease Type 2

Topic General Neurology

Presentation(s) P8 - Poster Session 8 (11:45 AM-12:45 PM)

Poster/Presentation
Number 7-006

Objective

To elucidate the role that GARS1 has on mitochondrial and lysosomal function and dynamics in Charcot Marie Tooth Disease Type 2.

Background GARS1 is an aminoacyl tRNA-synthetase which charges tRNA with the amino acid glycine as a crucial step in protein translation. Charcot Marie Tooth disease is an inheritable form of peripheral neuropathy that has no cure and includes over 100 subtypes of which Type 2 is linked to axonal degeneration. Autosomal dominant mutations in GARS1 lead to CMT Type 2D, but the mechanistic role of GARS1 in driving disease etiology is still not completely understood. Mitochondria and lysosomes can directly interact with one another at crucial hubs known as mitochondria-lysosome contact sites, which allow for their bidirectional regulation and dynamic crosstalk. However, the role and regulation of GARS1 at these contact sites, and in modulating mitochondrial and lysosomal function remains unclear.

Design/Methods To investigate novel cellular roles of GARS1 and the misregulation by CMT Type 2D associated mutations in GARS1, we utilized Super-Resolution live microscopy, immunofluorescence, and western blot.

Results We have found a new role for GARS1 in regulating the crosstalk between mitochondria and lysosomes. This may have important consequences for downstream mitochondrial and lysosomal function, and regulating their homeostasis. Importantly, this pathway is disrupted by CMT Type 2D associated mutations in GARS1, suggesting that misregulation of this key pathway may help contribute to the etiology of CMT Type 2D.

Conclusions GARS1 is a key protein which is misregulated in Charcot Marie Tooth disease Type 2D. Our study highlights a potential new role for GARS1 in regulating mitochondrial and lysosomal crosstalk, and demonstrates the importance of studying the mechanisms modulating this pathway. As multiple forms of aminoacyl tRNA-synthetases result in different genetic forms of CMT Type 2, this pathway may be a key driver of peripheral neuropathy.

Authors/Disclosures
Anika Gurbani PRESENTER	Miss Gurbani has nothing to disclose.
Anh M. Ly	Ms. Ly has nothing to disclose.
George C. Shum, Medical Student	Mr. Shum has nothing to disclose.
Yvette Wong, PhD	Dr. Wong has nothing to disclose.

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