Dataset Information

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

ABSTRACT:

Background

HSPB1 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 ?-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.

Methods

Patients 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.

Results

Frameshift 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.

Conclusion

Our results suggest that truncation of the non-conserved C-terminus impairs the function of HSPB1 in cellular stress response.

General significance

sHSPs 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.

SUBMITTER: Ylikallio E

PROVIDER: S-EPMC4661565 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Ylikallio Emil E Konovalova Svetlana S Dhungana Yogesh Y Hilander Taru T Junna Nella N Partanen Juhani V JV Toppila Jussi P JP Auranen Mari M Tyynismaa Henna H

BBA clinical 20150311

<h4>Background</h4>HSPB1 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.<h4>Meth ...[more]

PMID: 26675522

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Dataset Information

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

Background

Methods

Results

Conclusion

General significance

Publications

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

Similar Datasets

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