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HspB8 mutation causing hereditary distal motor neuropathy impairs lysosomal delivery of autophagosomes

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. © 2011 International Society for Neurochemistry.

Familial versus sporadic amyotrophic lateral sclerosis -A false dichotomy?

The role of RNA processing in the pathogenesis of motor neuron degeneration

Motor neurons are large, highly polarised cells with very long axons and a requirement for precise spatial and temporal gene expression. Neurodegenerative disorders characterised by selective motor neuron vulnerability include various forms of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A rapid expansion in knowledge on the pathophysiology of motor neuron degeneration has occurred in recent years, largely through the identification of genes leading to familial forms of ALS and SMA. The major emerging theme is that motor neuron degeneration can result from mutation in genes that encode factors important for ribonucleoprotein biogenesis and RNA processing, including splicing regulation, transcript stabilisation, translational repression and localisation of mRNA. Complete understanding of how these pathways interact and elucidation of specialised mechanisms for mRNA targeting and processing in motor neurons are likely to produce new targets for therapy in ALS and related disorders. © Cambridge University Press 2010.

Motor neuron disease

Another gene for ALS Mutations in sporadic cases and the rare variant hypothesis

Charcot-Marie-Tooth–Linked Mutant GARS Is Toxic to Peripheral Neurons Independent of Wild-Type GARS Levels

Familial versus sporadic amyotrophic lateral sclerosis--a false dichotomy?

Do twin studies still have anything to teach us about the genetics of amyotrophic lateral sclerosis?

TARDBP in amyotrophic lateral sclerosis: identification of a novel variant but absence of copy number variation

Normal d-dimer levels do not exclude the diagnosis of cerebral venous sinus thrombosis

Motor neuron disease: THE BARE ESSENTIALS

Motor neurone disease

Progressive unsteadiness in a 68-year-old man with longstanding abdominal pain and altered bowel habit

The study of rare diseases: butterfly collecting or an entree to understanding common conditions?

The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy

Asymmetrical late onset motor neuropathy associated with a novel mutation in the small heat shock protein HSPB1 (HSP27)

Characterisation of novel point mutations in the survival motor neuron gene SMN , in three patients with SMA

Treatment of vasculitic peripheral neuropathy: a retrospective analysis of outcome

Neuromuscular disorders: therapeutic advances