Pharmacological modulation of autophagy as treatment for inherited neuropathies.

Autophagy contributes to cellular homeostasis by promoting the bulk degradation of harmful misfolded proteins, aggregates and non-functional organelles from the cytoplasm. As molecular chaperones, small heat shock proteins (sHSP) operate in this pathway by assisting the formation of autophagy-competent vesicles, the autophagosomes. Mutations in the small heat shock protein HSPB1 disturb the formation of P62 bodies, the early seed necessary in the autophagic flux. Moreover, depletion of another family member, HSPB8, impairs the formation of P62 bodies. Mutations in HSPB1 and HSPB8 cause Charcot-Marie-Tooth disease or distal hereditary motor neuropathy, and both inherited peripheral neuropathies are currently untreatable. We aim to identify FDA/EMA-approved molecules that are able to reverse the autophagic deficits caused by mutant HSPB1 and HSPB8. We will validate the ability of the selected drugs to rescue the neurodegenerative phenotype in motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSC). We will provide new insights into the molecular pathology underlying mutations in sHSP and how the candidate drug pharmacologically modulates autophagy. The project as a whole aims to target autophagy, the first shared pathomechanism caused by different mutations in sHSP, occurring in CMT neuropathies.

Keywords:GENOTYPE-PHENOTYPE CORRELATION, GENETIC DISEASE

Disciplines:Neurological and neuromuscular diseases