Disease-causing mutations in the small heat shock protein Hsp27 alter its structure, chaperone activity, and protein interactome

Charcot Marie Tooth disease (CMT) and distal hereditary motor neuropathy (dHMN) are two heterogeneous and clinically overlapping diseases of the peripheral nervous system. Pathogenic mutations in various proteins including the small heat shock protein 27 (Hsp27, HSPB1) are associated with CMT and dHMN; however the molecular mechanisms underlying disease progression are not understood. Hsp27 is a ubiquitously expressed and highly conserved molecular chaperone that is involved in cytoprotective functions including protein homeostasis (proteostasis), redox modulation, inhibition of apoptosis, stabilisation of the cytoskeleton, and axonal transport. The mechanisms by which Hsp27 impacts these processes are largely unknown, as are the effects of disease-related mutations on the molecular structure and function of the protein. In an effort to better understand the roles of Hsp27 mutations in the development of CMT and dHMN, this thesis explores the effects of disease-causing mutations on the in vitro structure and chaperone activity of Hsp27, investigates the roles of Hsp27 in neuronal differentiation, mitochondrial maintenance and transport, and determines the interactome of Hsp27 and two disease-causing Hsp27 mutants in motor neuron-like cells.