Mechanistic Study Of Cerebellar Ataxia Caused By SNX14 Loss-of-function Mutations

Autosomal recessive cerebellar ataxias(ARCAs)is a common type of hereditary ataxia.Genetic evidence has shown that individuals carrying homozygous mutations in SNX14 exhibited early-onset ARCAs accompanied by significant cerebellar atrophy.However,due to the lack of appropriate animal models,the cellular and molecular mechanisms of SNX14 mutations in ARCAs remain unclear,let alone therapentic intervention.In this study,we generated a brain-specific Snxl4 knockout mouse model,and comprehensively analyzed its behavioral and morphological phenotypes,investigated the early-stage molecular events of cerebellar degeneration using transcriptomic analysis.Snxl4 conditioned knockout mice displayed progressive ataxia,characterized by poor balance and coordination.Morphological analysis showed that Snx14-deficient mice had smaller cerebellum,but with normal cerebral volume.Progressive loss of purkinje cells,which are critical for cerebellar motor learning and control,has been found in the cerebellum of Snx14 knockout mice,while cerebellar granule cells were not significant affected.Intriguing,in Snx14 knockout cerebellum,we also observed axonopathy in survived purkinje cells,as evidenced by the occurrence of axonal swellings containing accumulated organelles.These evidences suggested that deficiency of SANX14 causes cerebellar degeneration,which is mainly manifested by purkinje cell loss.In addition,we observed microglial activation in Snxl4 knockout mouse cerebellum,suggesting that purkinje cell death causes a secondary inflammatory response.To probe the initial molecular events,we performed transcriptomic analysis of 1-month Snxl4 knockout mouse cerebellum.It is interesting to find that down-regulation of several myelin associated gene expression.Electron microscopy indicated a thinner myelin sheath in the white matter of Snx14 knockout mouse cerebellum,but how Snx14 mutations cause myelin lesions,and whether the myelin lesions lead to purkinje cell death and cerebellar ataxia need to be further explored.In terms of treatment,we first found that intraperitoneal injection of valproic acid(VPA),an antiepileptic drug,largely reverse ataxia,purkinje cells loss and inflammatory response caused by Snx14 gene deletion,further investigation is required to determine the therapeutic target(s)of VPA in combating cerebellar neurodegeneration.In summary,SNX14 deletion cause cerebellar degeneration through affecting cerebellar purkinje cell death and myelin lesions,thus leading to cerebellar ataxia and cerebellar atrophy.VPA treatment reversed motor ataxia in Snx14 knockout mice by alleviating purkinje cell loss and inflammatory response.VPA treatment may bring a hope for intervention of the disease progress.