Truncated HSPB1 causes axonal neuropathy and impairs tolerance to unfolded protein stress

• C-terminal truncation of small heat shock protein HSPB1 causes neuropathy.
• Truncated HSPB1 is stable in patient fibroblasts and binds wild type HSPB1.
• C-terminus of HSPB1 is critical for tolerance to unfolded protein stress.
• Neuropathy may develop as a consequence of impaired cellular stress response.

BackgroundHSPB1 belongs to the family of small heat shock proteins (sHSP) that have importance in protection against unfolded protein stress, in cancer cells for escaping drug toxicity stress and in neurons for suppression of protein aggregates. sHSPs have a conserved α-crystalline domain (ACD), flanked by variable N- and C-termini, whose functions are not fully understood. Dominant missense variants in HSPB1, locating mostly to the ACD, have been linked to inherited neuropathy.MethodsPatients underwent detailed clinical and neurophysiologic characterization. Disease causing variants were identified by exome or gene panel sequencing. Primary patient fibroblasts were used to investigate the effects of the dominant defective HSPB1 proteins.ResultsFrameshift variant predicting ablation of the entire C-terminus p.(Met169Cfs2*) of HSPB1 and a missense variant p.(Arg127Leu) were identified in patients with dominantly inherited motor-predominant axonal Charcot–Marie–Tooth neuropathy. We show that the truncated protein is stable and binds wild type HSPB1. Both mutations impaired the heat stress tolerance of the fibroblasts. This effect was particularly pronounced for the cells with the truncating variant, independent of heat-induced nuclear translocation and induction of global transcriptional heat response. Furthermore, the truncated HSPB1 increased cellular sensitivity to protein misfolding.ConclusionOur results suggest that truncation of the non-conserved C-terminus impairs the function of HSPB1 in cellular stress response.General significancesHSPs have important roles in prevention of protein aggregates that induce toxicity. We showed that C-terminal part of HSPB1 is critical for tolerance of unfolded protein stress, and when lacking causes axonal neuropathy in patients.

A truncating variant in the small heat shock protein HSPB1 causes neuropathy, which leads to distal weakness and sensory impairment in hands and feet. HSPB1 is important for the unfolded protein response. Cultured patient skin cells suffered and died when subjected to unfolded protein stress, whereas cells from a healthy person survived. These results demonstrate that biochemical abnormalities related to neuropathy manifest in skin cells, and suggest that neuropathy may develop as a consequence of decreased stress tolerance.Figure optionsDownload as PowerPoint slide