Proposed Therapy for Neurodegenerative Diseases May Cause Early-onset CMT, Study Suggests

A proposed therapy for neurodegenerative diseases involving the removal of the neurofilament light chain protein (NEFL) may have harmful consequences in humans, potentially leading to Charcot-Marie-Tooth disease (CMT), researchers have found.

The research team discovered this while studying the effects of a type of mutation in the NEFL gene, called a nonsense mutation, which they found resulted in a complete absence of NEFL and caused early-onset CMT.

Their findings were published in the study, “Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy,” in the journal Neurology Genetics.

NEFL is a key subunit of neurofilaments, which are major components in the structure of nerve cells. Toxic accumulation of neurofilaments is a hallmark of many neurodegenerative diseases, which is why NEFL removal has been previously proposed as a possible treatment option.

NEFL is particularly abundant in axons, where it plays a key role in their growth during development, the maintenance of axon caliber, and the transmission of electrical impulses along axons.

Mutations in the NEFL gene are behind CMT. Most of these are known as dominant mutations, meaning that only one copy of the mutation is sufficient to cause the disease.

Researchers in this study set out to investigate the effects on non-dominant, or recessive, mutations in the NEFL gene. They looked specifically at recessive nonsense mutations, or defects that introduce a premature stop sign while the NEFL protein is being produced.

They used motor neurons differentiated from induced pluripotent stem cells of a patient with early-onset CMT carrying a novel nonsense mutation in NEFL.

The patient and her sibling were diagnosed with CMT1 subtype F (CMT1F) early in infancy, and showed severely reduced nerve conduction velocities and slowly progressive muscle weakness in the arms and legs.

In the cells from this CMT patient, the expression of the NEFL gene was markedly reduced compared with controls. Consequently, the NEFL protein was absent in the patient’s neurons.

Despite this, “they were still able to form as long, branching projections as the control neurons, suggesting that the intermediate filament network in the absence of NEFL was sufficient for axonal maintenance in culture,” the researchers wrote.

This suggests that the intermediate filament formation in cultured neurons does not require NEFL, they said.

“We propose that the neurofilament accumulation, a common feature of many neurodegenerative diseases, mimics the absence of NEFL seen in recessive CMT if aggregation prevents the proper localization of wild-type NEFL in neurons,” the researchers wrote.

“Our results suggest that the removal of NEFL as a proposed treatment option is harmful in humans,” the study concluded.