Molecular Neurobiology

, Volume 47, Issue 1, pp 90–104 | Cite as

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

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


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.


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



Spinocerebellar ataxia type 2




Spinal bulbar muscular atrophy


Huntington’s disease


Spinocerebellar ataxia


Spinocerebellar ataxia type 1


Spinocerebellar ataxia type 3


Spinocerebellar ataxia type 6


Spinocerebellar ataxia type 7


Spinocerebellar ataxia type 17


Spinocerebellar ataxia type 10


Olivopontocerebellar atrophy


Rapid eye movement


Amyotrophic lateral sclerosis


Parkinson disease


Multiple system atrophy


Like Sm domain


Lsm-associated domain


PABPC interacting motif-2


Ataxin-2 domain protein


Polyadenylate-binding protein


Ataxin-2 homolog in yeast


PABP homolog in yeast


Ataxin-2-binding protein




Long-term potentiation


RNA-binding motif protein 9


RNA-binding protein with multiple splicing


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


Ryanodine receptor


Dentatorubral–pallidoluysian atrophy


Ubiquitin–proteasome system


Short-hairpin RNA


Adeno-associated virus serotype 1


RNA interference


Antisense oligonucleotide


Central nervous system



This work was supported by CONACyT-México, Grant No. 128418 (B.C.).

Conflict of interest

The authors declare that there are no conflicts of interest.


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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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