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

Abstract

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

Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons

“…This rare neuropathy primarily affects the peripheral sensorimotor systems, leading to distal sensory loss, muscle weakness, and atrophy. The mechanism behind how these mutations induce axonopathy remains elusive ( BasuRay et al., 2010 , Cherry et al., 2013 , Cogli et al., 2010 , Janssens et al., 2014 , Liu and Wu, 2017 , Spinosa et al., 2008 ). We wondered whether our findings of late endosome-associated axonal translation, especially of mRNAs essential for mitochondrial and axonal integrity, could be relevant to understanding CMT2B.…”

NOTCH-induced rerouting of endosomal trafficking disables regulatory T cells in vasculitis

“…RAB7 participates in the formation of the late endosome and lysosome and is required for exosome biogenesis (24,25). RAB7 mutations result in Charcot-Marie-Tooth (CMT) type 2 neuropathies (26). RAB11 facilitates the formation and fusion of recycling endosomes to the plasma membrane (27), contributes to host innate immunity in bacterial and viral infection (28) and is associated with neurodegenerative disease (29).…”

Rab GTPases: Switching to Human Diseases

“…In contrast with these studies, work done on D. melanogaster suggested that CMT2B is a consequence of a partial loss-of-function of Rab7a, as expression of CMT2B mutants does not cause neuropathy-like phenotypes [141]. This raised the questions as to whether Drosophila is a good model for CMT2B or whether more optimal models, such as rodents and human neurons, are needed to more accurately define the mechanisms of the disease [142].…”