Spinocerebellar ataxia type 2 (part B): molecular pathogenesis and therapeutic perspectives
Keywords:
Spinocerebellar ataxia type 2, ataxin-2, nuclear and citoplasmatic foci, molecular mechanisms,, genic therapyAbstract
Spinocerebellar ataxia type 2 (SCA2) is an autosomal inherited neurodegenerative disorder
characterized by a multisystemic phenotype with somatic and autonomic nervous system
manifestations. SCA2 is caused by the expansion of a CAG triplet repeat located in the 5’
coding region of the ATXN2 gene, which results in the incorporation of a segment of polyglu-
tamines in the mutant protein, being longer expansions associated with earlier onset and more
severe disease in subsequent generations of a given genealogy. In this review, we present the
experimental evidence that has helped to define the molecular mechanisms underlying SCA2
pathogenesis. In addition, we recapitulate data showing the participation of ataxin-2 in crucial
cellular processes, including messenger RNA maturation, translation regulation, endocytosis
and calcium-mediated signaling. Finally, based on the molecular basis of SCA2 pathogenesis,
we discuss the perspectives of development of therapeutic strategies for SCA2.
Publication Facts
Reviewer profiles N/A
Author statements
Indexed in
- Editor & editorial board
- profiles
- Academic society
- N/A
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
References
Velázquez-Pérez L, Rodríguez-Labrada R, García-Rodrí-
guez JC, Almaguer-Mederos LE, Cruz-Mariño T, Laffi ta-
Mesa JM. A Comprehensive review of spinocerebellar
ataxia type 2 in Cuba. Cerebellum. 2011; 10 (2): 184-198.
Magaña JJ, Velázquez-Pérez L, Cisneros B. Spinoce-
rebellar ataxia type 2: clinical presentation, molecular
mechanisms, and therapeutic perspectives. Mol Neu-
robiol. 2013; 47: 90-104.
Auburger GW. Spinocerebellar ataxia type 2. Handb
Clin Neurol. 2012; 103: 423-436.
Saleem Q, Choudhry S, Mukerji M, Bashyam L, Pad-
ma MV, Chakravarthy A et al. Molecular analysis of
autosomal dominant hereditary ataxias in the Indian
population: high frequency of SCA2 and evidence for
a common founder mutation. Hum Genet. 2000; 106:
-187.
Velázquez-Pérez L, García R, Santos FN, Paneque HM,
Medina HE, Hechavarría PR. Epidemiology of Cuban
hereditary ataxias. Rev Neurol. 2001; 32: 606-611.
Alonso E, Martínez-Ruano L, DeBiase I, Mader C, Ochoa
A, Yescas P et al. Distinct distribution of autosomal do-
minant spinocerebellar ataxia in the Mexican population.
Mov Disord. 2007; 22: 1050-1053.
Magaña JJ, Tapia-Guerrero YS, Velázquez-Pérez L,
Cerecedo-Zapata CM, Maldonado-Rodríguez M, Ja-
no-Ito J et al. Analysis of CAG repeats in fi ve SCA loci
in Mexican population: epidemiological evidence of a
SCA7 founder effect. Clin Genet. 2014; 85: 159-165.
Magaña JJ, Vergara MD, Sierra-Martínez M, García-
Jiménez E, Rodríguez-Antonio F, Gómez M del R et al.
Molecular analysis of the CAG repeat among patients
with type-2 spinocerebellar ataxia in the Mexican pop-
ulation. Gac Med Mex. 2008; 144: 413-418.
Sahba S, Nechiporuk A, Figueroa KP, Nechiporuk T,
Pulst SM. Genomic structure of the human gene for spi-
nocerebellar ataxia 2 (SCA2) on chromosome 12q24.1.
Genomics. 1998; 47: 359-364.
Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasa-
ki H et al. Identifi cation of the spinocerebellar ataxia type
gene using a direct identifi cation of repeat expansion
and cloning technique, DIRECT. Nat Genet. 1996; 14:
-284.
Mao R, Aylsworth AS, Potter N, Wilson WG, Brening-
stall G, Wick MJ et al. Childhood-onset ataxia: testing
for large CAG-repeats in SCA2 and SCA7. Am J Med
Genet. 2002; 110: 338-345.
Giunti P, Sabbadini G, Sweeney MG, Davis MB, Vene-
ziano L, Mantuano E et al. The role of SCA2 trinucleotide
repeat expansion in 89 autosomal dominant cerebellar
ataxia families: frequency, clinical and genetics cor-
relates. Brain. 1998; 121: 459-467.
Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu
Rev Neurosci. 2007; 30: 575-621.
Ellegren H. Heterogeneous mutation processes in hu-
man microsatellite DNA sequences. Nat Genet. 2000;
: 400-402.
Bauer PO, Nukina N. The pathogenic mechanisms of
polyglutamine diseases and current therapeutic strate-
gies. J Neurochem. 2009; 110: 1737-1765.
Magaña JJ, Cisneros B. Perspectives on gene therapy
in myotonic dystrophy type 1. J Neurosci Res. 2011; 89:
-285.
Van de Loo S, Eich F, Nonis D, Auburger G, Nowock J.
Ataxin-2 associates with rough endoplasmic reticulum.
Exp Neurol. 2009; 215: 110-118.
Turnbull VJ, Storey E, Tarlac V, Walsh R, Stefani D, Clark
R et al. Different ataxin-2 antibodies display different immu-
noreactive profi les. Brain Res. 2004; 1027 (1-2): 103-116.
Huynh DP, Del Bigio MR, Ho DH, Pulst SM. Expression
of ataxin-2 in brains from normal individuals and patients
with Alzheimer’s disease and spinocerebellar ataxia 2.
Ann Neurol. 1999; 45 (2): 232-241.
Rubinsztein DC, Wyttenbach A, Rankin J. Intracellular
inclusions, pathological markers in diseases caused by
expanded polyglutamine tracts? J Med Genet. 1999; 36
(4): 265-270.
Taroni F, DiDonato S. Pathways to motor incoordination: the
inherited ataxias. Nat Rev Neurosci. 2004; 5 (8): 641-655.
Koyano S, Iwabuchi K, Yagishita S, Kuroiwa Y, Uchihara
T. Paradoxical absence of nuclear inclusion in cerebellar
Purkinje cells of hereditary ataxias linke to CAG expansion.
J Neurol Neurosurg Psychiatry. 2002; 73 (4): 450-452.
Kretzschmar D, Tschäpe J, Bettencourt Da Cruz A,
Asan E, Poeck B, Strauss R et al. Glial and neuronal
expression of polyglutamine proteins induce behavioral
changes and aggregate formation in drosophila. Glia.
; 49 (1): 59-72.
Boy J, Schmidt T, Schumann U, Grasshoff U, Unser S,
Holzmann C. A transgenic mouse model of spinocere-
bellar ataxia type 3 resembling late disease onset and
gender-specifi c instability of CAG repeats. Neurobiol
Dis. 2010; 37 (2): 284-293.
Albrecht M, Golatta M, Wullner U, Lengauer T. Structural
and functional analysis of ataxin-2 and ataxin-3. Eur J
Biochem. 2004; 271: 3155-3170.
Satterfi eld TF, Pallanck LJ. Ataxin-2 and its drosophila
homolog, ATX2, physically assemble with polyribo-
somes. Hum Mol Genet. 2006; 15: 2523-2532.
Tharun S. Roles of eukaryotic Lsm proteins in the reg-
ulation of mRNA function. Int Rev Cell Mol Biol. 2009;
: 149-189.
Ralser M, Albrecht M, Nonhoff U, Lengauer T, Lehrach
H, Krobitsch S. An integrative approach to gain insights
into the cellular function of human ataxin-2. J Mol Biol.
; 346: 203-214.
Bravo J, Aguilar-Henonin L, Olmedo G, Guzmán P.
Four distinct classes of proteins as interaction part-
ners of the PABC domain of Arabidopsis thaliana
Poly(A)-binding proteins. Mol Genet Genomics. 2005;
: 651-665.
Shibata H, Huynh DP, Pulst SM. A novel protein with
RNA-binding motifs interacts with ataxin-2. Hum Mol
Genet. 2000; 9: 1303-1313.
Lee JA, Tang ZZ, Black DL. An inducible change in Fox-
/A2BP1 splicing modulates the alternative splicing of
downstream neuronal target exons. Genes Dev. 2009;
: 2284-2293.
Tsien JZ, Huerta PT, Tonegawa S. The essential role of
hippocampal CA1 NMDA receptor-dependent synaptic
plasticity in spatial memory. Cell. 1996; 87: 1327-1338.
Lim J, Hao T, Shaw C, Patel AJ, Szabo G, Rual JF et al.
A protein-protein interaction network for human inherited
ataxias and disorders of Purkinje cell degeneration. Cell.
; 125: 801-814.
Kozlov G, Safaee N, Rosenauer A, Gehring K. Structural
basis of binding of P-body-associated proteins GW182
and ataxin-2 by the Mlle domain of poly(A)-binding
protein. J Biol Chem. 2010; 285: 13599-13606.
Ciosk R, DePalma M, Priess JR. ATX-2, the C. elegans
ortholog of ataxin 2, functions in translational regulation
in the germline. Development. 2004; 131: 4831-4841.
Vernet C, Artzt K. STAR, a gene family involved in signal
transduction and activation of RNA. Trends Genet. 1997;
: 479-484.
Swisher KD, Parker R. Localization to, and effects of
Pbp1, Pbp4, Lsm12, Dhh1, and Pab1 on stress gran-
ules in saccharomyces cerevisiae. PLoS One. 2010; 5:
e10006.
Huynh DP, Scoles DR, Nguyen D, Pulst SM. The autoso-
mal recessive juvenile Parkinson disease gene product,
parkin, interacts with and ubiquitinates synaptotagmin
XI. Hum Mol Genet. 2003; 12: 2587-2597.
Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi
R. An unfolded putative transmembrane polypeptide,
which can lead to endoplasmic reticulum stress, is a
substrate of Parkin. Cell. 2001; 105: 891-902.
Ralser M, Nonhoff U, Albrecht M, Lengauer T, Wanker
EE, Lehrach H et al. Ataxin-2 and huntingtin interact with
endophilin-A complexes to function in plastin-associated
pathways. Hum Mol Genet. 2005; 14: 2893-2909.
Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY,
Dikic I. Cbl-CIN85-endophilin complex mediates ligand
induced downregulation of EGF receptors. Nature. 2002;
: 183-187.
Satterfi eld TF, Jackson SM, Pallanck LJ. A drosophila
homolog of the polyglutamine disease gene SCA2 is a
dosage-sensitive regulator of actin fi lament formation.
Genetics. 2002; 162: 1687-1702.
Huynh DP, Figueroa K, Hoang N, Pulst SM. Nuclear lo-
calization or inclusion body formation of ataxin-2 are not
necessary for SCA2 pathogenesis in mouse or human.
Nat Genet. 2000; 26: 44-50.
Aguiar J, Fernández J, Aguilar A, Mendoza Y, Vazquez
M, Suárez J et al. Ubiquitous expression of human SCA2
gene under the regulation of the SCA2 self promoter
cause specifi c Purkinje cell degeneration in transgenic
mice. Neurosci Lett. 2006; 392: 202-206.
Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP et
al. Deranged calcium signaling and neurodegeneration
in spinocerebellar ataxia type 2. J Neurosci. 2009; 29:
-9162.
Pirker W, Back C, Gerschlager W, Laccone F, Alesch
F. Chronic thalamic stimulation in a patient with spinoc-
erebellar ataxia type 2. Mov Disord. 2003; 18: 222-225.
Freund HJ, Barnikol UB, Nolte D, Treuer H, Auburger
G, Tass PA et al. Subthalamic-thalamic DBS in a case
with spinocerebellar ataxia type 2 and severe tremor-A
unusual clinical benefi t. Mov Disord. 2007; 22: 732-735.
Ristori G, Romano S, Visconti A, Cannoni S, Spadaro
M, Frontali M et al. Riluzole in cerebellar ataxia: A
randomized, double-blind, placebo-controlled pilot
trial (CME) (LOE Classifi cation). Neurology. 2010; 74:
-845.
Bonini NM, La Spada AR. Silencing polyglutamine de-
generation with RNAi. Neuron. 2005; 48: 715-718.
Matilla-Dueñas A, Sánchez I, Corral-Juan M, Dávalos A,
Alvarez R, Latorre P. Cellular and molecular pathways
triggering neurodegeneration in the spinocerebellar
ataxias. Cerebellum. 2010; 9: 148-166.
Wong HK, Bauer PO, Kurosawa M et al. Blocking ac-
id-sensing ion channel 1 alleviates Huntington’s disease
patology via an ubiquitin-proteosome system-dependent
mechanism. Hum Mol Genet. 2008; 17: 3223-3235.
Pollitt SK, Pallos J, Shao J, Desai UA, Ma AA, Thompson
LM et al. A rapid cellular FRET assay of polyglutamine
aggregation identifi es a novel inhibitor. Neuron. 2003;
: 685-694.
Wood NI, Pallier PN, Wanderer J, Morton AJ. Systemic
administration of Congo red does not improve motor or
cognitive function in R6/2 mice. Neurobiol Dis. 2007;
: 342-353.
Karpuj MV, Becher MW, Springer JE, Chabas D,
Youssef S, Pedotti R et al. Prolonged survival and
decreased abnormal movements in transgenic model
of Huntington disease, with administration of the trans-
glutaminase inhibitor cystamine. Nat Med. 2002; 8:
-149.
Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante
KL, Jenkins BG, Hersch SM et al. Therapeutic effects
of coenzyme Q10 and remacemide in transgenic mouse
models of Huntington’s disease. J Neurosci. 2002; 22:
-1599.
Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S et
al. Minocycline inhibits caspase-1 and caspase-3 expres-
sion and delays mortality in a transgenic mouse model of
Huntington disease. Nat Med. 2000; 6: 797-801.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra
This work is licensed under a Creative Commons Attribution 4.0 International License.
© Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra under a Creative Commons Attribution 4.0 International (CC BY 4.0) license which allows to reproduce and modify the content if appropiate recognition to the original source is given.
