This report describes spinocerebellar ataxia 2 (SCA2 or SCA2/ALS13), which is a subtype of spinocerebellar ataxia; SCA2 is inherited as an autosomal dominant. The human gene implicated in this disease is ATXN2. SCA2 is one of a number spinocerebellar ataxias caused by expansion of CAG repeats within the coding region of the causative gene, resulting in an expanded run of glutamine (Q) residues in the encoded protein. Expanded (CAG)n repeats in ATXN2 are also associated with a susceptibility to amyotrophic lateral sclerosis 13 (OMIM:183090), and with a susceptibility to late-onset Parkinson disease (OMIM:168600); ALS13 is now treated as a form of SCA2 by OMIM. There is one high-scoring fly ortholog, Atx2, for which multiple genetic reagents have been generated including classical amorphic alleles, overexpression and RNAi targeting constructs, and alleles caused by insertional mutagenesis. Dmel\Atx2 is orthologous to a second human gene, ATXN2L.
Multiple UAS constructs of the human Hsap\ATXN2 gene have been introduced into flies, including ATXN2 genes with expanded (CAG)n repeats, and genes containing deletions of protein domains. Assaying eye phenotypes, expression of the Hsap\ATXN2 gene with the pathogenic polyQ expansion enhances phenotypes observed for a model of ALS10 (FBhh0000017).
Variants implicated in this human disease have been assessed using transgenic constructs of the human gene; see the 'Disease-Implicated Variants' table below. Variant described as (CAG)n EXPANSION, INTERMEDIATE are in the range associated with ALS13. A construct with a LONG (CAG)n repeat expansion has been introduced into flies and has been made available, but it has not been characterized. (Longer expansions (>33) are described as associated with SCA2, and intermediate expansions (27-33) with symptoms of ALS13). Some resources describe ALS13 as a form of SCA2 (OMIM:183090).
Animals homozygous for loss-of-function alleles of Dmel\Atx2 die, usually during the larval stage; germline clones result in female sterility; somatic clones result in visible phenotypes and tissue loss. RNAi experiments implicate Atx2 in maintenance of circadian rhythms. Experiments using Atx2 constructs in which the polyQ or other intrinsically disordered regions have been deleted suggest that these regions are dispensable for the essential functions of the Atx2 protein, but are necessary for long-term memory formation/consolidation; they appear to support RNP-granule assembly in neurons. Physical and genetic interactions have been described for Dmel\Atx2; see below and in the gene report for Atx2.
Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).
[updated Jul. 2021 by FlyBase; FBrf0222196]
The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003, pubmed:14628900). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]
The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias' (SCAs). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord; the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From OMIM:164400, 2015.10.27]
[SPINOCEREBELLAR ATAXIA 2; SCA2](https://omim.org/entry/183090)
[ATAXIN 2; ATXN2](https://omim.org/entry/601517)
Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements and, in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration. [From GeneReviews, Spinocerebellar Ataxia Type 2, pubmed:20301452 2015.12.14]
This form of autosomal dominant spinocerebellar ataxia, SCA2, is caused by an expanded (CAG)n trinucleotide repeat in ATXN2, the gene encoding ataxin-2. Unaffected individuals have 13 to 31 CAG repeats, whereas affected individuals have 32 to 79 repeats, with some in the range of 500 repeats (summary by Almaguer-Mederosa et al., 2010, pubmed:20095980). There is also an association between 29 or more CAG repeats and the development of amyotrophic lateral sclerosis-13 (ALS13). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (OMIM:105400). [From OMIM:183090, 2015.10.27]
Genetic, biochemical, and neuropathologic interactions between TDP43 (OMIM:605078), a protein involved in amyotrophic lateral sclerosis (ALS10; OMIM:612069), and ATXN2, which raised the possibility that mutations in ATXN2 may have a causative role in ALS. The ATXN2 polyQ tract length, although variable, is most frequently 22-23, with expansions of greater than 34 causing SCA2. However, the variable nature of the polyQ repeat indicated a mechanism by which such mutations in ATXN2 could be linked to ALS. Elden et al. (2010, pubmed:20740007) proposed that intermediate-length expansions greater than 23 but below the threshold for SCA2 may be associated with ALS. PolyQ expansions in ATXN2 enhance its interaction with TDP43. Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. It has been proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress (Elden et al., 2010, pubmed:20740007). [From OMIM:183090, 2015.12.14]
Ortholog of human ATXN2 and ATXN2L (1 Drosophila to 2 human).
Dmel\Atx2 shares 24% identity and 36% similarity with human ATXN2, and 25% identity and 36% similarity to human ATXN2L.