Spinocerebellar Ataxia Type 2: Clinicogenetic Aspects, Mechanistic Insights, and Management Approaches

Abstract

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits.

Keywords: ataxin-2; autosomal dominant cerebellar ataxias; hereditary ataxias; polyglutamine expansions; spinocerebellar ataxia type 2.

Figure 1

Epidemiological features of spinocerebellar ataxia type 2 (SCA2). (A) Relative frequency of SCA2 around the world. (B) Prevalence rates of SCA2 in Cuba.

Figure 2

Stages of spinocerebellar ataxia type 2 (SCA2) progression. CST, corticospinal tract; PA, prism adaptation; REM, rapid eye movement; RLS, restless legs syndrome; PLMS, periodic leg movements syndrome; MN, motor neuron; RWA, REM sleep without atonia.

Figure 3

MRI of sagital (left) and coronal (right) examples of (A) normal brain, (B) spinocerebellar ataxia type 2 (SCA2) patient with early clinical manifestation, and (C) SCA2 patient with full ataxia manifestation. Note the severe cerebellar volume loss in gray and white matter in advanced stages of the disease.

Figure 4

Physiological functions of ataxin-2. (A) Promotion of mRNA translation of specific genes via its interaction with the PABP and 3′ untranslated regions in the polyribosomes; (B) global suppression of translation under stress conditions via its interaction with the miRNA pathway proteins Ago1 and Me31b; (C) control of endocytosis through its binding to endophilins; (D) regulation of the calcium signaling pathway through the control of translation of some of their components; and (E) sensoring of nutritional and energetic state of the cells through the direct and/or indirect inhibition of the mTORC1 signaling pathway. Atxn2, Ataxin-2; PABP, polyA binding protein; eIF3, eukaryotic initiation factor 3; eIF4A, eukaryotic initiation factor4A; eIF4E, eukaryotic initiation factor 4E; IF4G1, eukaryotic initiation factor 4G1; Ago1, Argonuate 1; Me31b, Deadbox helicase me31B; SERCA2, smooth endoplasmic reticulum Ca-ATP-ase 2; INPP5A, inositol polyphosphate-5-phosphatase; Atp2a2, gene encoding the SERCA2 protein; RORA, retinoic acid-related orphan receptor alpha; PI3K, phosphoinositide 3-kinase; mTOR, mechanistic target of rapamycin; ITPR1, inositol triphosphate receptor 1; RPS6, ribosomal protein S6; 4E-BP, eIF4E-binding protein.