During the last decade, mutations in three small heat shock proteins (Hsps) HSPB1, HSPB3 and HSPB8 have been identified as causative of distal hereditary motor neuropathy (dHMN). Hsps are a ubiquitously expressed family of molecular chaperones with versatile functions that include refolding of misfolded proteins. Hsp70, the archetypal ATP-dependent Hsp, binds misfolded proteins with weak affinity. J domain (HSP40) proteins bind to HSP70, thereby increasing its protein binding and refolding capacity. In 2008, an autosomal recessive form of dHMN was described due to homozygous mutations in the Hsp40 gene, HSJ1. We have preliminary evidence that HSJ1 knockout mice develop de novo motor neuron (MN) degeneration, providing a model for this new form of dHMN. In this study, MNs from HSJ1 +/+ and HSJ1 −/− mice have been examined in vitro in primary MN cultures. We examined the effects of HSJ1 ablation on the stress response in MNs. We found that HSJ−/− MNs display an enhanced ER stress response compared to +/+ MNs in response to heat shock. Thus, HSJ−/− cells upregulate the expression of ER stress markers, such as the ER resident heat shock protein BiP. We also examined functional markers of MN function including axonal transport but found that the transport of mitochondria in HSJ −/− cells was unaffected. Thus, HSJ −/− primary motoneurons display some of the pathological hallmarks of dHMN and therefore can be a suitable model to study the mechanism of disease.
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