Pathogenic mechanisms underlying spinocerebellar ataxia type 1

Abstract

The family of hereditary cerebellar ataxias is a large group of disorders with heterogenous clinical manifestations and genetic etiologies. Among these, over 30 autosomal dominantly inherited subtypes have been identified, collectively referred to as the spinocerebellar ataxias (SCAs). Generally, the SCAs are characterized by a progressive gait impairment with classical cerebellar features, and in a subset of SCAs, accompanied by extra-cerebellar features. Beyond the common gait impairment and cerebellar atrophy, the wide range of additional clinical features observed across the SCAs is likely explained by the diverse set of mutated genes that encode proteins with seemingly disparate functional roles in nervous system biology. By synthesizing knowledge obtained from studies of the various SCAs over the past several decades, convergence onto a few key cellular changes, namely ion channel dysfunction and transcriptional dysregulation, has become apparent and may represent central mechanisms of cerebellar disease pathogenesis. This review will detail our current understanding of the molecular pathogenesis of the SCAs, focusing primarily on the first described autosomal dominant spinocerebellar ataxia, SCA1, as well as the emerging common core mechanisms across the various SCAs.

Keywords: ATXN1; Ataxin-1; CAG/polyglutamine disorder; Neurodegeneration; Repeat expansion; SCA1; Spinocerebellar ataxia.

Fig. 1

Protein organization of ataxin-1. Schematic displaying the key domains of human ataxin-1 protein. Post-translational modification sites are displayed above the protein with key enzymes involved in the modification displayed on the right. Interactors of ataxin-1 are displayed below the domain with which they interact

Fig. 2

Summary of SCA1 transgenic and knock-in mouse RNA-sequencing. Summary of findings from transcriptional profiling of the cerebellum, pons, and medulla of SCA1 Purkinje cell-specific transgenic mouse (Pcp2-ATXN1[82Q]) and Atxn1^154Q/2Q (knock-in) mice throughout disease [108, 110, 111]. Pathways in bold represent commonly perturbed pathways across multiple tissues within a given model at that time point. RNA-sequencing of the medulla was performed on either the inferior olivary nucleus (IO) alone [110], or the IO and hypoglossal nucleus (IO + XII) [111]