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Project

A preclinical study to treat neuromuscular disease caused by HSPB8 mutations (MDA577497).

The small heat shock protein B8 (HSPB8) belongs to the 'stress protein family' and is expressed in various tissues and cells. HSPB8 acts as a molecular chaperone by clearing protein aggregates and reducing their toxic accumulation. This protective function has been studied in the context of cancer and neurodegenerative disease. We were the first to report disease causing mutations in the HSPB8 gene in patients with distal hereditary motor neuropathy, a variant of Charcot-Marie-Tooth neuropathy. Patients have a progressive degeneration of their peripheral nerves resulting in muscle weakness and atrophy. We generated a mouse model mimicking the human distal motor neuropathy by introducing a known disease causing mutation in the HSPB8 gene (a knock-in mouse). In addition we also made a model in which we deleted HSPB8 (a knock-out mouse) and these animals develop a mild myopathy. This project aims to identify therapeutic compounds that can rescue or delay the neurodegeneration observed in the knock-in model, or that can result in a milder phenotype as seen in the knock-out animals. The identified small molecule compound acting on the expression of HSPB8 could be beneficial to treat patients affected with distal hereditary motor neuropathy, but also patients with distal myopathies and related neuromuscular disorders.
Date:1 Aug 2018 →  31 Jul 2021
Keywords:NEUROMUSCULAR DISEASES
Disciplines:Genetics, Systems biology, Molecular and cell biology, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing