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

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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.

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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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Acknowledgments

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

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Authors and Affiliations

  1. Department of Genetics, National Rehabilitation Institute (INR), Mexico City, Mexico

    J. J. Magaña

  2. Center for the Research and Rehabilitation of the Hereditary Ataxias (CIRAH), Holguín, Cuba

    L. Velázquez-Pérez

  3. Department of Genetics and Molecular Biology, CINVESTAV-IPN, Av. Instituto Politécnico Nacional No. 2508, Col. San Pedro Zacatenco, 07360, Mexico City, México

    B. Cisneros

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  1. J. J. Magaña
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  3. B. Cisneros
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Magaña, J.J., Velázquez-Pérez, L. & Cisneros, B. Spinocerebellar Ataxia Type 2: Clinical Presentation, Molecular Mechanisms, and Therapeutic Perspectives. Mol Neurobiol 47, 90–104 (2013). https://doi.org/10.1007/s12035-012-8348-8

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