Purkinje cell degeneration in Marinesco-Sjogren syndrome: role of cell stress, alterations of proteostasis and calcium homeostasis

Marinesco-Sjogren syndrome (MSS) is a very rare, early-onset, autosomal recessive disease characterized by difficulties in motor coordination and speech, muscle weakness, which impairs autonomous standing and walking, and frequent congenital bilateral cataracts. These symptoms become more severe with time, then stabilise allowing an almost normal life-span. To date, MSS is not treatable and patient care is limited to rehabilitative cures. Recently, the SIL1 gene was identified as responsible for the majority of MSS cases. Sil1 mutations lead to death of several cell types, among which important neurons in the cerebellum, causing the main symptoms of the disease. However, the disease mechanisms are still unknown, and this represents a major obstacle for developing an effective treatment. The neurons that degenerate in MSS are involved in many pathologies, therefore studying the mechanisms leading to their degeneration could provide important information also for other diseases. Our idea is to generate cell models of MSS and look for functional alterations potentially involved in neuronal death. The results obtained in the cell models will be validated in a mutant mouse that recapitulates the main features of the disease, and that could also be used to test potential pharmacological treatments. These studies are expected to improve our knowledge of how Sil1 mutations lead to MSS, and provide essential information for devising effective therapeutic strategies.