Dysregulation of the TRK-Fused Gene (TFG)/ULK1/LC3 axis in Hereditary Motor and Sensory Neuropathy with Proximal dominant involvement (HMSN-P), recessive hereditary Spastic Paraplegia (SPG 57), and Charcot-Marie-Tooth disease 2 (CMT2)

Mutations in the TRK-Fused Gene (TFG) are known to be associated with the pathogenesis of three degenerative diseases: the Hereditary Motor and Sensory Neuropathy with Proximal predominance (HMSN-P), a complex form of recessive hereditary Spastic Paraplegia (SPG57), and the Charcot-Marie-Tooth disease 2 (CMT2). Defective autophagy appears to centrally contribute to the pathogenesis of these neuropathies and increasing evidence suggests that aggrephagy plays a relevant role. We previously demonstrated that TFG: i) interacts with ULK1, to regulate its stability and localisation; ii) it is crucial for the association of isolation membrane components and LC3BII during autophagosomes formation, thus regulating autophagy execution; iii) is a novel interactor of LC3 family members, by preferentially binding LC3C. In addition, TFG mutations are often coupled to alteration of mitochondrial morphology and function, and result in the formation of protein aggregates containing TFG itself and, among others, the autophagy receptors optineurin and sequestosome 1 (SQSTM1, p62). This evidence pointed out to an impairment in the autophagy machinery, which could be particularly relevant for the activation/execution of selective autophagy, such as mitophagy and aggrephagy. We recently identified a patient carrying a new TFG mutation (L366F), in the identified TFG LIR domain (AA 361-366, PGFTSL), necessary for TFG interaction with LC3. We investigated the impact of this mutation, as compared to the already described ones, on autophagy, mitophagy, and aggrephagy.