Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system, and mutations in neurofilaments have been linked to some forms of CMT. Neurofilaments are the major intermediate filaments of neurones, but the mechanisms by which the CMT mutations induce disease are not known. Here, we demonstrate that CMT mutant neurofilaments disrupt both neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurones. We also show that CMT mutant neurofilaments perturb the localization of mitochondria in neurones. Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and diabetic neuropathy. Our results demonstrate that aberrant neurofilament assembly and transport can induce neurological disease, and further implicate defective neurofilament metabolism in the pathogenesis of human neurodegenerative diseases.

Neurofilament light chain polypeptide gene mutations in Charcot–Marie–Tooth disease: nonsense mutation probably causes a recessive phenotype

“…13 Functional studies have shown that missense mutant NEFL proteins disrupt the assembly with wild-type NEFL and with the NEFM and NEFH, and cause aggregation, resulting in the disruption of axonal neurofilament translocation and anterograde or retrograde axonal transport including mitochondria. [14][15][16] In this study, we found a homozygous nonsense mutation, Glu140-Stop, in one patient (case 2) in addition to four heterozygous missense mutations in five other patients. The parents of case 2 were first cousins, but they never complained of muscle weakness.…”

NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1

“…CMT1 is characterized by demyelination and slow nerve conduction velocities (NCVs), whereas CMT2 is characterized by signs of axonal regeneration and normal or slightly reduced NCVs (Harding and Thomas 1980). Neurofilament light chain polypeptide (NEFL), which consists of an N-terminal head, a central road, and a C-terminal tail domain, is one of the most abundant cytoskeletal components in the neuron (Brownlees et al 2002). Several missense mutations in the NEFL gene have been reported, and a number of these have been predicted to produce alterations in the formation of the intermediate filament network in neurons (Pérez-Ollé et al 2005;Sasaki et al 2006).…”

Salsolinol, a tetrahydroisoquinoline-derived neurotoxin, induces oxidative modification of neurofilament-L: protection by histidyl dipeptides

“…Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy affecting motor and sensory nerves of the peripheral nervous system (29). In CMT, disruption of assembly and aggregation of NF-L occur from mutations of NF-L (30,31). Recently, it was reported that CMT mutations of NF-L and small heat-shock protein B1 have similar disruptive effects on the NF network, leading to aggregation of NF-L protein with progressive degeneration and loss of viability of motor neurons (32).…”