Abstract
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by balance and gait disturbance, muscle coordination deficits, and dysarthria as a primary symptom. SCA1 is caused by the expansion of CAG repeats in the ATXN1 gene, leading to a polyglutamine(polyQ) tract in the Ataxin-1 protein. In this study, the effects of KDS2010, an inhibitor of monoamine oxidase-B (MAO-B), were evaluated in a transgenic mouse model of SCA1 (SCA1(154Q/2Q)) disease model using the rotarod, hindlimb, and open field tests. In both males and females, oral administration of KDS2010 significantly improved latency in the rotarod test and the hindlimb clasping phenotype without changing muscle weight. In the open field test, a notable improvement in moving distance was observed particularly in females. Treatment with KDS2010 slowed molecular layer atrophy and restored the reduced number of Purkinje cells in the cerebellum of SCA1 model mice, accompanied by decreased levels of glial fibrillary acidic protein (GFAP) and reduced expression of monoamine oxidase-B (MAO-B). These results indicate that KDS2010 ameliorated the behavioral pathology of SCA1 by attenuating GFAP upregulation and preventing Purkinje cell loss. Our findings demonstrate that KDS2010 improves SCA1-related behavioral deficits by reducing GFAP expression, preserving Purkinje cell numbers, and decreasing cerebellar MAO-B levels-molecular markers of SCA1, without affecting muscle size.