Abstract
Over the years, a diverse range of animal models has been established and employed in both basic and translational research, elucidating the intricate molecular mechanisms that drive cerebellar ataxias. However, many preclinical models remain insufficiently characterised, hindering our understanding of the diseases and the development of effective therapeutic approaches. The present study provides a comprehensive phenotypic and molecular characterisation of the woozy (Sil1(wz)) mouse model of Marinesco-Sjögren Syndrome (MSS), a rare autosomal recessive cerebellar ataxia characterised by cerebellar dysfunction, congenital cataracts, and progressive myopathy. Disease progression was monitored from 5 to 26 weeks using a series of motor assessments, including the accelerating rotarod, beam walking, pole test, and inverted grid test. These evaluations revealed progressive cerebellar ataxia in Sil1(wz) mice, with symptoms emerging around the ninth week of age. A clear sex-related difference was observed in the motor tests, with female Sil1(wz) mice outperforming their male counterparts across all assessments. Histological analysis revealed significant muscular atrophy in glycolytic muscles (gastrocnemius and quadriceps) but not in oxidative muscles (soleus) of 26-week-old Sil1(wz) mice. Molecular analyses confirmed the upregulation of unfolded protein response markers (BiP and pEIF2α) and proteolysis-associated proteins (Rab11 and LC3-II) in glycolytic but not oxidative muscles. Cognitive assessment using nesting behaviour showed deficits in Sil1(wz) mice at 14 weeks, assuming similarities with mental retardation shown by MSS patients. Our findings established a comprehensive timeline of disease progression in this MSS model and highlighted the differential vulnerability of glycolytic versus oxidative muscles and cerebellar regions. These insights pave the way for the development of therapeutic strategies for MSS and related cerebellar ataxias.