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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This work was supported by CONACyT-México, Grant No. 128418 (B.C.).
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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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DOI: https://doi.org/10.1007/s12035-012-8348-8