gms | German Medical Science

Abnormal accumulations of misfolded proteins that elicit endoplasmic reticulum (ER) stress are major pathological hallmarks of Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Mutations in the endoplasmic reticulum (ER) chaperon sigma receptor 1 (SigR1) cause familial ALS and FTLD. Several reports also suggested an involvement of SigR1 in HD. We recently found that SigR1 shows altered localization, abnormal modification and loss of function in sporadic ALS. The present study further defines, how SigR1 is involved in neuronal survival, maintenance and connectivity and how these functions are altered in ALS and HD. Here we focussed on the protein aggregation, alterations of the ER and of autophagy pathways in neuronal somata and axons in ALS and HD. Since autophagy has been shown to be tightly linked to ER function and is decisive in neurodegeneration, we further showed the regulation of autophagy pathway by SigR1 and their agonists. Altogether we propose that SigR1 plays an important role in Neuronal survival and maintenance and abnormal modifications in SigR1 might leads to neuropathological phenotypes involving altered ER structure and functions.