HDAC6 inhibition alleviates mitochondrial trafficking in novel 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. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant 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 altered distribution of mitochondria in axons. To identify the molecular basis of these defects, we performed an unbiased quantitative proteomic screen of the endogenous MFN2 interactome, which revealed candidate MFN2 interactors implicated in MFN2-mediated regulatory signalling, cytoskeletal scaffolding, and ubiquitin-ligase machinery. Importantly, we showed that mitochondrial trafficking defects can be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also significantly rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Embryonic Stem Cell

SUBMITTER: Mark Collins  

LAB HEAD: Mark Collins

PROVIDER: PXD077751 | Pride | 2026-06-15

REPOSITORIES: Pride