TFG mutation induces haploinsufficiency and drives axonal Charcot–Marie–Tooth disease by causing neurite degeneration

Abstract

Aims TFG‐related axonal Charcot–Marie–Tooth (CMT) disease is a late‐onset, autosomal dominant, hereditary motor, and sensory neuropathy characterized by slowly progressive weakness and atrophy of the distal muscles. The objective of this study was to determine the common pathogenic mechanism of TFG‐related CMT type 2 (CMT2) caused by different mutations and establish a direct association between TFG haploinsufficiency and neurodegeneration. Methods Three individuals carrying the TFG p.G269V mutation but with varying disease durations were studied. The effect of the p.G269V mutation was confirmed by analyzing protein samples extracted from the blood of two individuals. The functional consequences of both CMT2 mutant gene products were evaluated in vitro. The effect of TFG deficiency in the nervous system was examined using zebrafish models and cultured mouse neurons. Results Overexpression of p.G269V TFG failed to enhance soluble TFG levels by generating insoluble TFG aggregates. TFG deficiency disrupted neurite outgrowth and induced neuronal apoptosis both in vivo and in vitro and further impaired locomotor capacity in zebrafish, which was consistent with the phenotype in patients. Wnt signaling was activated as a protective factor in response to TFG deficiency. Conclusion CMT2‐related TFG mutation induces TFG haploinsufficiency within cells and drives disease by causing progressive neurite degeneration.

Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias

“…Progressive motor phenotype with uncoordinated gait, and degeneration not only of long spinal axons, but also of spinocerebellar and cerebellar granule axons [51] Malformations with a curved body axis, reduced motor capacity, high mortality, significant increase in neuronal apoptosic cells in both brain and spinal cord [76] The study of neurodegenerative diseases in vitro has typically used primary neuronal cultures derived from embryonic or adult nervous tissue. However, the obviously limited availability of patient-derived biopsies is rarely compatible with the average sample size needed for setting up experimental conditions strictly required to generate robust data.…”