Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?
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.
Department of Neurosciences, University of California San Diego, Medical Teaching Facility, Room 312 MC-0624, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA. hul023@ucsd.edu.
Harry
H
Liu
Department of Neurosciences, University of California San Diego, Medical Teaching Facility, Room 312 MC-0624, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA. chw049@ucsd.edu.
Chengbiao
C
Wu
D001369:Axons / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism*; D056726:Genetic Association Studies; D006801:Humans; D000083083:Laminopathies; D009113:Muramidase / Q000378:metabolism; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D020932:Nerve Growth Factor; D009113:Muramidase; D020691:rab GTP-Binding Proteins
CMT2B; NGF; Rab7; autophagy; axons; lysosomes; mutations; peripheral sensory neuropathy