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Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder caused by polyglutamine repeat expansions in Ataxin-1. Recent evidence supports a role for microRNA (miRNAs) deregulation in SCA1 pathogenesis. However, the extent to which miRNAs may modulate the onset, progression or severity of SCA1 remains largely unknown. In this study, we used a mouse model of SCA1 to determine if miRNAs are misregulated in pre- and post-symptomatic SCA1 cerebellum. We found a significant alteration in the steady-state levels of numerous miRNAs prior to and following phenotypic onset. In addition, we provide evidence that increased miR-150 levels in SCA1 Purkinje neurons may modulate disease pathogenesis by targeting the expression of Rgs8 and Vegfa.

A major challenge in treating lysosomal storage diseases with enzyme therapy is correcting symptoms in the central nervous system (CNS). This study used a murine model of mucopolysaccharidosis type VII (MPS VII) to test whether pathological and functional CNS defects could be corrected by expressing beta-glucuronidase via bilateral intrastriatal injection of adeno-associated virus type 5 (AAV5betagluc) vectors. After injecting AAV5betagluc, different brain regions expressed active beta-glucuronidase, which corrected lysosomal storage defects. Compared to age-matched littermates, adult MPS VII mice were impaired in spatial learning and memory, as measured by the repeated acquisition and performance chamber (RAPC) assay. AAV5betagluc-treated MPS VII mice improved significantly in the RAPC assay, relative to saline-injected littermates. Moreover, our studies reveal that cognitive changes in MPS VII mice correlate with decreased N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor expression. Importantly, AAV5betagluc delivery restored glutamate receptor levels. Together, these data demonstrate that AAV5 vectors deliver a therapeutically effective beta-glucuronidase gene to the CNS and further suggest a possible mechanism underlying spatial learning defects in MPS VII mice.

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