Exploring the roles of autophagy regulation and mitochondria homeostasis in Okinawa-type HMSN, molecular mechanisms and clinical opportunities

TFG mutations have been implicated in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), in a complex form of recessive hereditary spastic paraplegia (SPG57), and in Charcot-Marie-Tooth disease 2 (CMT2). Okinawa-type hereditary motor and sensory neuropathy (HMSNO), an autosomal dominant neurodegenerative disorder characterized by young adult onset of proximal or distal muscle weakness and atrophy with later onset of distal sensory impairment, associates with p.Pro285Leu (P285L) TFG mutation. As of today, the molecular mechanisms by which TFG mutations lead to the onset and progression of these diseases are still unknown, and there is no therapeutical strategy to cure or even ameliorate patients’ conditions. We hypothesise that the p.Pro285Leu (P285L) mutation may on different TFG-dependent activity in the cell by increasing its aggregation propensity, as well as impairing regulation of both autophagy and mitochondrial quality control. Here we propose to get further insights P285L pathological role, by investigating TFG-dependent regulation of autophagy as well as the impact on mitochondrial homeostasis. This molecular dissection would allow a better understanding on TFG functions in peripheral neurons, and identify new molecular target, that may pave the way for developing specific therapeutic strategies.