Exploration of preventive drugs for spinocerebellar ataxia using cultured cerebellar Purkinje cells

Abstract

Neurodegenerative diseases are caused by progressive degeneration of specific neurons. To overcome neurodegenerative diseases, the exploitation of preventive drugs is strongly expected, since impaired neurons are not regenerated by drugs. Spinocerebellar ataxia (SCA) is a group of dominantly inherited neurodegenerative diseases and is characterized by the progressive cerebellar ataxia. To date, SCA is classified into SCA1-48 by the variance of causal genes. Since SCA patients are commonly characterized by cerebellar ataxia and atrophy of cerebellum, it is possible that there are common pathogenic mechanisms in SCAs. However, there are not any shared functions among SCA-causing proteins. Cerebellar Purkinje cells (PCs) are sole output neurons from cerebellar cortexes, crucial for cerebellar functions and characterized highly branched dendrites. During the exploration of the molecular pathogenesis of several SCA-causing proteins, we found that several SCA-causing proteins commonly trigger the impairment of dendritic development of primary cultured cerebellar PCs. Dendritic shrinkage of cerebellar PCs has been observed and is considered to be related to the motor dysfunction in several SCA model mice. Therefore, we assume that impaired dendritic development of cultured cerebellar Purkinje cells is one of the common phenotypes of SCA in vitro and that cultured PCs expressing SCA-causing proteins could be in vitro SCA models. This SCA model would be useful for the efficient exploration of novel preventive drugs against various types of SCAs.