Molecular Neurobiology

, Volume 47, Issue 1, pp 90–104

Spinocerebellar Ataxia Type 2: Clinical Presentation, Molecular Mechanisms, and Therapeutic Perspectives

  • J. J. Magaña
  • L. Velázquez-Pérez
  • B. Cisneros
Article

Abstract

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant genetic disease characterized by cerebellar dysfunction associated with slow saccades, early hyporeflexia, severe tremor of postural or action type, peripheral neuropathy, cognitive disorders, and other multisystemic features. SCA2, one of the most common ataxias worldwide, is caused by the expansion of a CAG triplet repeat located in the N-terminal coding region of the ATXN2 gene, which results in the incorporation of a segment of polyglutamines in the mutant protein, being longer expansions associated with earlier onset and more sever disease in subsequent generations. In this review, we offer a detailed description of the clinical manifestations of SCA2 and compile the experimental evidence showing the participation of ataxin-2 in crucial cellular processes, including messenger RNA maturation and translation, and endocytosis. In addition, we discuss in the light of present data the potential molecular mechanisms underlying SCA2 pathogenesis. The mutant protein exhibits a toxic gain of function that is mainly attributed to the generation of neuronal inclusions of phosphorylated and/or proteolytic cleaved mutant ataxin-2, which might alter normal ataxin-2 function, leading to cell dysfunction and death of target cells. In the final part of this review, we discuss the perspectives of development of therapeutic strategies for SCA2. Based on previous experience with other polyglutamine disorders and considering the molecular basis of SCA2 pathogenesis, a nuclei-acid-based strategy focused on the specific silencing of the dominant disease allele that preserves the expression of the wild-type allele is highly desirable and might prevent toxic neurodegenerative sequelae.

Keywords

Spinocerebellar ataxia type 2 Ataxin-2 Molecular mechanisms Polyglutamines Trinucleotide repeats Gene therapy 

Abbreviations

SCA2

Spinocerebellar ataxia type 2

polyQ

Polyglutamine

SBMA

Spinal bulbar muscular atrophy

HD

Huntington’s disease

SCA

Spinocerebellar ataxia

SCA1

Spinocerebellar ataxia type 1

SCA3

Spinocerebellar ataxia type 3

SCA6

Spinocerebellar ataxia type 6

SCA7

Spinocerebellar ataxia type 7

SCA17

Spinocerebellar ataxia type 17

SCA10

Spinocerebellar ataxia type 10

OPCA

Olivopontocerebellar atrophy

REM

Rapid eye movement

ALS

Amyotrophic lateral sclerosis

PD

Parkinson disease

MSA

Multiple system atrophy

Lsm

Like Sm domain

LsmAD

Lsm-associated domain

PAM2

PABPC interacting motif-2

A2D

Ataxin-2 domain protein

PABP

Polyadenylate-binding protein

Pbp1

Ataxin-2 homolog in yeast

Pab1

PABP homolog in yeast

A2BP1

Ataxin-2-binding protein

RNP

Ribonucleoprotein

LTP

Long-term potentiation

RBM9

RNA-binding motif protein 9

RBPMS

RNA-binding protein with multiple splicing

InsP3R1

Type 1 inositol (1,4,5)-triphosphate receptor

RyanR1

Ryanodine receptor

DRPLA

Dentatorubral–pallidoluysian atrophy

UPS

Ubiquitin–proteasome system

shRNA

Short-hairpin RNA

AAV1

Adeno-associated virus serotype 1

RNAi

RNA interference

AON

Antisense oligonucleotide

CNS

Central nervous system

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • J. J. Magaña
    • 1
  • L. Velázquez-Pérez
    • 2
  • B. Cisneros
    • 3
  1. 1.Department of GeneticsNational Rehabilitation Institute (INR)Mexico CityMexico
  2. 2.Center for the Research and Rehabilitation of the Hereditary Ataxias (CIRAH)HolguínCuba
  3. 3.Department of Genetics and Molecular BiologyCINVESTAV-IPNMexico CityMéxico

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