Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?

摘要: Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction degeneration of neurons major clinical manifestation CMT2B. However, the cellular molecular pathogenic mechanisms remain undefined. CMT2B caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that mutation(s) enhances levels activated proteins, thus resulting increased lysosomal activity autophagy. As consequence, trafficking signaling neurotrophic factors such as nerve growth factor (NGF) long axons are particularly vulnerable to premature degradation. A “gain toxicity” model has, thus, been proposed based on these observations. studies fly photo-sensory indicate causes “loss function”, haploinsufficiency. In review, we summarize experimental for both hypotheses. We argue better models (rodent animals human neurons) needed precisely define mechanisms.