HDAC6 inhibition partially alleviates mitochondrial trafficking defects and restores motor function in human motor neuron and zebrafish models of Charcot-Marie-Tooth Disease Type 2A

Abstract

Charcot Marie Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. There are currently no treatments for this debilitating disease. To investigate disease mechanisms and facilitate treatment discovery, here we developed an in vitro model for CMT type 2A by introducing the patient-specific MFN2R94Q mutation into human embryonic stem cells (hESCs). Isogenic mutant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in reduced numbers of mitochondria in distal parts of axons. Importantly, we showed that mitochondrial trafficking defects can be alleviated by treatment with an HDAC6 inhibitor. Chemical and genetic inhibition of HDAC6 also significantly rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a mutation-specific insight into CMT2A disease mechanism and confirms HDAC6 as a promising target for further therapeutic development.

Hereditary Neuropathies

“…Multiple gene therapy approaches, including gene silencing (CMT1A), allele-specific silencing (CMT2E), gene replacement (CMTX1, CMT4A, CMT4C, CMT2A), gene editing with CRISPR-Cas9 (CMT1A, CMT2A, CMT2D-F), and antisense oligonucleotides (CMT1A) are under development. Some approaches, such as small molecules, enzyme replacements, and antioxidants, target common downstream pathways in hereditary neuropathies 94-97 …”

“…Some approaches, such as small molecules, enzyme replacements, and antioxidants, target common downstream pathways in hereditary neuropathies. [94][95][96][97] CONCLUSION Hereditary neuropathies encompass a spectrum of motor and sensory neuropathies with axonal or demyelinating features caused by genetic defects that affect various nerve functions. Hereditary neuropathies continue to be classified by phenotype; therefore, thorough clinical evaluation and electrophysiology are essential in diagnosing patients.…”