Chaperone dysfunction leading to the build-up of misfolded proteins could frequently be linked to clinical manifestations also affecting the nervous system and the skeletal muscle. In addition, increase in chaperone function is beneficial to antagonize protein aggregation and thus represents a promising target for therapeutic concepts for many genetic and acquired chaperonopathies. However, little is known on the precise molecular mechanisms defining the cell and tissue abnormalities in the case of impaired chaperone function as well as on underlying effects in the case of compensatory up-regulation of chaperones. This scarcity of knowledge often arises from a lack of appropriate animal models that mimic closely the human molecular, cellular, and histological characteristics. Here, we introduce the Sil1-mutant woozy mouse as a suitable model to investigate molecular and cellular mechanisms of impaired ER-chaperone function affecting the integrity of nervous system and skeletal muscle. The overlapping clinical findings in man and mouse indicate that woozy is a good copy of a human phenotype called Marinesco-Sjögren syndrome. We confirm the presence of ER-stress and expand the biochemical knowledge of altered nuclear envelope in muscle, a hallmark of SIL1-disease. In addition, our data suggest that impaired excitation-contraction coupling might be part of the SIL1-pathophysiology. Our results moreover indicate that divergent expression of pro- and anti-survival proteins is decisive for Purkinje cell survival. By summarizing the current knowledge of woozy, we focus on the suitability of this animal model to study neuroprotective co-chaperone function and to investigate the involvement of co-chaperones in the predisposition of other disorders such as diabetic neuropathy.
Keywords: BiP; cerebellar ataxia; chaperone; vacuolar myopathy; woozy mouse.