New Approaches in Studies of the Molecular Pathogenesis of Type 2 Spinocerebellar Ataxia
- PDF / 626,400 Bytes
- 14 Pages / 594 x 792 pts Page_size
- 4 Downloads / 191 Views
New Approaches in Studies of the Molecular Pathogenesis of Type 2 Spinocerebellar Ataxia P. A. Egorova and I. B. Bezprozvanny
Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 105, No. 11, pp. 1349–1372, November, 2019. Original article submitted August 8, 2019. Revised version received August 15, 2019. Accepted August 16, 2019. 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. Keywords: type 2 spinocerebellar ataxia, polyglutamine tract diseases, cerebellum, calcium signaling, aggregation.
Type 2 spinocerebellar ataxia (SCA2) is a genetic disease with autosomal dominant inheritance and is due to expansion of CAG triplets in the ubiquitously expressed gene ATXN2, which encodes ataxin-2 protein with an extended polyglutamine tract [1–5]. The pathophysiological signs of SCA2 include progressive cerebellar atrophy and subsequent gradually increasing ataxia [2]. There is as yet no disease-modifying therapy for SCA2, such that SCA2 patients are supported exclusively by symptomatic therapy and palliative medical approaches. Ataxin-2 protein, the protein produced by the gene mutated in SCA2, has various functions within cells, including an involvement in RNA metabolism [6]. A number of model systems in cells, yeasts, worms, flies, mice, and neurons from induced pluripotential
stem cells (iPSC) from SCA2 patients have been developed to study the bases of the pathology of SCA2. In SCA2 in mice and patients, the primary damage is to Purkinje cells (PC) in the cerebellar cortex and the conducting tracts of the cerebellum. Studies in these model sys
Data Loading...
