Premium
HspB8 mutation causing hereditary distal motor neuropathy impairs lysosomal delivery of autophagosomes
Author(s) -
Kwok Alice S.,
Phadwal Kanchan,
Turner Bradley J.,
Oliver Peter L.,
Raw Annie,
Simon Anna Katharina,
Talbot Kevin,
Agashe Vishwas R.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07521.x
Subject(s) - autophagy , peripheral blood mononuclear cell , flow cytometry , biology , microbiology and biotechnology , mutation , pathology , mutant , homeostasis , medicine , gene , biochemistry , apoptosis , in vitro
J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07521.x Abstract HspB8, a small heat‐shock protein implicated in autophagy, is mutated in patients with distal hereditary motor neuropathy type II (dHMNII). Autophagy is essential for maintaining protein homeostasis in the central nervous system, but its role has not been investigated in peripheral motor neurons. We used a novel, multispectral‐imaging flow cytometry assay to measure autophagy in cells. This assay revealed that over‐expression of wild‐type HspB8 in motor neuron‐like NSC34 cells led to an increased co‐localisation of autophagosomes with the lysosomes. By contrast, over‐expression of mutant HspB8 resulted in autophagosomes that co‐localised with protein aggregates but failed to co‐localise with the lysosomes. A similar impairment of autophagy could also be demonstrated in peripheral blood mononuclear cells from two dHMNII patients with the HspB8 K141E mutation. We conclude that defects in HspB8‐mediated autophagy are likely to contribute to dHMNII pathology and their detection in peripheral blood mononuclear cells could be a useful, accessible biomarker for the disease.