*2.4. Charcot-Marie-Tooth Disease*

Mutations of LRSAM1 (leucine-rich repeat and sterile alpha motif containing 1), an E3 ligase with RING ZINC finger domains and leucine-rich repeats, are associated with cases of early-onset Parkinson's disease [105] and to Charcot-Marie-Tooth disease [62] (Table 1). Charcot-Marie-Tooth disease affects the peripheral nervous system and is characterized by progressive muscular atrophy. Knockdown of *Lrsam1* in zebrafish leads to disturbed neurodevelopment with a less organized neural structure and affected tail formation and movement. *Lrsam1* mutant mice present a normal neuromuscular structure and only mild neuropathy phenotype in aged mice, but higher sensitivity to neurotoxic agents that cause axonal degeneration [106].

Mechanistically, LRSAM1 promotes monoubiquitination of TSG101, a component of the endosomal sorting complex required for transport (ESCRT)-1. LRSAM1-mediated monoubiquitination of TSG101 enables recycling of TSG101-containing sorting complexes and cargo reloading [60]. Several proteins directly regulating post-translational processing and intracellular trafficking, such as tripartite motif-containing 2 (TRIM2) and RAS-related small GTPase RAB7, are also found to be mutated in Charcot-Marie-Tooth disease, confirming the link between vesicle trafficking and Charcot-Marie-Tooth disorder [61].
