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Project

Targeting and delineating autophagic deficits caused by small heat shock protein mutations in CMT.

Small heat shock proteins (sHSP) prevent the formation and accumulation of toxic protein aggregates in cells and help to clear these aggregates through autophagy. Mutations in the small heat shock protein HSPB1 disturb the formation of SQSTM1/P62 bodies, an important structure in the process of the autophagic flux. Also 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 (IPN) 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 effect of the selected drugs in motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSC) with the aim to improve the neurodegenerative phenotype. In parallel with the drug screening, we will characterize the role of sHSPs in autophagosome formation, thereby providing insights in the molecular mechanism of this pathway. In summary, this project aims to target autophagy, the first shared pathomechanism between these two genes, and contributes to our understanding of the underlying molecular deficits.
Date:1 Nov 2019 →  31 Oct 2023
Keywords:AUTOPHAGY
Disciplines:Molecular and cell biology not elsewhere classified, Neurological and neuromuscular diseases, Compound screening
Project type:Collaboration project