gms | German Medical Science

Question: SIL1 functions as a co-chaperone for the major chaperon of the endoplasmic reticulum (ER) called BiP. A decade ago, recessive mutations within SIL1 could be linked to the manifestation of Marinesco-Sjögren syndrome (MSS), a disorder affecting the central nervous system and skeletal muscles. In the past two years, we could define a varying phenotypical and mutational spectrum of MSS, comprehensively characterized the muscle pathology and contributed to revealing a neuroprotective role of elevated SIL1 in ALS. In contrast to this, recently others reported a neuroprotective effect of SIL1 depletion by rescuing Tau hyperphosphorylation on ER stress. These controversy effects of SIL1 level prompted us to study the overall molecular consequences of SIL1 increase and depletion more precisely in order to get insights into the functional spectrum of SIL1 expression in neuroprotection.

Methods and results: We generated stable in vitro models of SIL1-overexpression and depletion, respectively. Using these models comprehensive cell biological, morphological, biochemical and unbiased proteome studies were carried out. Our results revealed a profound role of SIL1 far beyond ER-homeostasis, indicating that SIL1 expression modulates the vesicular transport machinery, the cytoskeleton as well as mitochondrial and proteasomal function. Moreover, activation of pro- and anti-apoptotic mechanisms could be detected. These results were not only verified by cell biological assays but also by in vivo studies using Sil1-deficient lumbal spinal cord.

Conclusions: Remarkably, disturbances of these cellular functions – especially depicted by a variety of proteins altered upon SIL1-depletion – could already be linked to the pathophysiology of different neuropathological disorders including ALS. These profound insights are particularly emphasized by modified abundances of different disease-associated proteins like VAPB and VCP. Thus, our combined results shed light on the problem of beneficial and adverse cellular consequences of altered SIL1 expression in both, health and disease.