Held Up in Traffic—Defects in the Trafficking Machinery in Charcot-Marie-Tooth Disease

Abstract

Charcot-Marie-Tooth disease (CMT), also known as motor and sensory neuropathy, describes a clinically and genetically heterogenous group of disorders affecting the peripheral nervous system. CMT typically arises in early adulthood and is manifested by progressive loss of motor and sensory functions; however, the mechanisms leading to the pathogenesis are not fully understood. In this review, we discuss disrupted intracellular transport as a common denominator in the pathogenesis of different CMT subtypes. Intracellular transport via the endosomal system is essential for the delivery of lipids, proteins, and organelles bidirectionally to synapses and the soma. As neurons of the peripheral nervous system are amongst the longest neurons in the human body, they are particularly susceptible to damage of the intracellular transport system, leading to a loss in axonal integrity and neuronal death. Interestingly, defects in intracellular transport, both in neurons and Schwann cells, have been found to provoke disease. This review explains the mechanisms of trafficking and subsequently summarizes and discusses the latest findings on how defects in trafficking lead to CMT. A deeper understanding of intracellular trafficking defects in CMT will expand our understanding of CMT pathogenesis and will provide novel approaches for therapeutic treatments.

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

“…Dynamic regulation of mitochondrial form and transport is critical in long peripheral axons, and its defects are one of the main pathways affected in CMT ( Markworth et al, 2021 ). NFL is shown to interact with Myosin Va (MyoVa) and, therefore, function as an anchor through the MyoVa interaction for mitochondria and other organelles ( Rao et al, 2002 ; Rao et al, 2011 ).…”

Mitf is a Schwann Cell Sensor of Axonal Integrity that Drives Nerve Repair

“…inhibitor Ndrg1 mutated in CMT4D 19,20 , the Rab11 effector SH3TC2 mutated in CMT4C 21,22 , and the PI(3)P phosphatase MTMR2 mutated in CMT4B [23][24][25] . Taken together, the genes linked to CMT4 suggest that second messenger signaling via lipid phosphoinositides may control how SCs respond to extracellular cues 26,27 . While it is clear that plasticity is critical for repair following injury, the role for plasticity in neural disease remains enigmatic.…”

Dynein dysfunction prevents maintenance of high concentrations of slow axonal transport cargos at the axon terminal: a computational study

“…Dynein mutations are associated with many cases of malformations of cortical development, spinal muscular atrophy with lower extremity dominance, and congenital muscular dystrophy. Another example is Charcot-Marie-Tooth (CMT) disease that affects peripheral motor and sensory neurons [5]. CMT type 2O disease is caused by a mutation in gene DYNC1H1 that encodes the dynein heavy chain [5][6][7][8].…”

“…Another example is Charcot-Marie-Tooth (CMT) disease, a disorder of peripheral motor and sensory neurons [5]. CMT type 2O disease is caused by a mutation in gene DYNC1H1 that encodes the dynein heavy chain [5][6][7][8].…”

“…Another example is Charcot-Marie-Tooth (CMT) disease, a disorder of peripheral motor and sensory neurons [5]. CMT type 2O disease is caused by a mutation in gene DYNC1H1 that encodes the dynein heavy chain [5–8]. Although the involvement of molecular motors in CMT pathogenesis is not surprising – long sensory and motor neurons require a large anterograde flux of various cargos from the soma to support their remote terminals [9] – an intriguing question is why degeneration of these neurons is associated with dynein dysfunction.…”