Artikel
The endoplasmic reticulum (ER) co-chaperone SIL1 in human sporadic and familial ALS
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Veröffentlicht: | 14. September 2016 |
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Gliederung
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Introduction: Abnormal accumulations of misfolded proteins that elicit endoplasmic reticulum(ER) stress are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). Mutation of the ER co-chaperon SIL1 causes Marinesco-Sjögren syndrome, which is characterized by cerebellar degeneration, cataracts and vacuolar myopathy. Recent studies by us and others showed that SIL1 mutation leads to specific ER alterations in patients and mice and that SIL1 regulates MN subtype-selective ER stress in ALS. Results obtained with G93A-SOD1 transgenic ALS mice suggest that Sil1 protects neurons from ER stress and subsequent autophagy.
Objectives: How SIL1 is implicated in neuronal survival and maintenance in human ALS patients.
Results: We focused on alterations of the ER and associated functions including autophagy pathways in neuronal somata and proximal and distal axons as well as muscle fibers in human sporadic and familial ALS. We showed that SIL1 was involved in MN survival from damage elicited by ER stress and by abnormal accumulation of misfolded TDP-43, FUS, matrin-3 and other proteins linked to ALS pathogenesis. Furthermore we found that SIL1 was associated with the Nissl substance of alpha-MNs and accumulates at C-terminal synapses in ALS (Figure 1 [Fig. 1]). These synapses are known to provide compensatory synaptic plasticity during MN - interneuron degeneration.
Conclusion: Altogether our result suggests that SIL-1 serves as a neuroprotective factor in both mouse model and human ALS by several specific ways which largely involves the ER and associated functions.