New Approaches in Studies of the Molecular Pathogenesis of Type 2 Spinocerebellar Ataxia

Abstract

Type 2 spinocerebellar ataxia (SCA2) is an inherited progressive disease whose cause at the genetic level is an expansion of the polyglutamine tract in ataxin-2 protein. Effective treatment and disease-modifying therapy remain unavailable to patients with SCA2. Patients are currently given only symptomatic treatment, along with palliative medical care. With the aim of seeking new therapeutic targets for treatment of SCA2, many scientific groups have tried to study the physiological, molecular, and biochemical changes to cerebellar neurons in patients with SCA2 and in various model systems. State-of-the-art approaches to studies of the pathogenesis of SCA2 have yielded new data on the molecular mechanisms of the disease and have suggested possible strategies for the potential treatment of this disease. The present review summarizes current data on the genetic basis of SCA2, describes the known properties and functions of ataxin-2 protein, considers the mechanisms of degeneration of cerebellar cortex cells, impairments to their physiological function, and associated damage to the conducting pathways of the cerebellum, and presents data on contemporary model systems used for studies of the basis of SCA2; we also present information on novel approaches to studies of the molecular mechanisms underlying the pathology of SCA2 such as aggregation, oxidative stress, and damage to cell signaling and calcium signaling, and consider the role of autophagy and the microglia in the molecular pathogenesis of SCA2.