Purkinje Cell Expression of a Mutant Allele of<i>SCA1</i>in Transgenic Mice Leads to Disparate Effects on Motor Behaviors, Followed by a Progressive Cerebellar Dysfunction and Histological Alterations

TLDR

Spinocerebellar ataxia type 1 is an autosomal dominant neurological disorder caused by a CAG repeat expansion that encodes a polyglutamine tract. The study investigates the behavioral and neuropathological progression in transgenic mice expressing a mutant SCA1 allele. At five weeks, mutant mice exhibit impaired rotarod performance without balance deficits yet show increased exploratory activity, and with age they develop progressive incoordination, Purkinje dendritic and somatic atrophy with minimal cell loss, indicating that ataxia results from early cellular dysfunction and morphological changes rather than neuron death.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract. Work presented here describes the behavioral and neuropathological course seen in mutant SCA1 transgenic mice. Behavioral tests indicate that at 5 weeks of age mutant mice have an impaired performance on the rotating rod in the absence of deficits in balance and coordination. In contrast, these mutant SCA1 mice have an increased initial exploratory behavior. Thus, expression of the mutant SCA1 allele within cerebellar Purkinje cells has divergent effects on the motor behavior of juvenile animals: a compromise of rotating rod performance and a simultaneous enhancement of initial exploratory activity. With age, these animals develop incoordination with concomitant progressive Purkinje neuron dendritic and somatic atrophy but relatively little cell loss. Therefore, the eventual development of ataxia caused by the expression of a mutant SCA1 allele is not the result of cell death per se, but the result of cellular dysfunction and morphological alterations that occur before neuronal demise.