FB2020_03, released Jun 16, 2020
Human Disease Model Report: spinocerebellar ataxia 1
FB2020_03, released Jun 16, 2020
Human Disease Model Report: spinocerebellar ataxia 1
Human Disease Model Report: spinocerebellar ataxia 1
Human Disease Model Report: spinocerebellar ataxia 1
This report describes spinocerebellar ataxia 1 (SCA1), which is a subtype of spinocerebellar ataxia; SCA1 is inherited as an autosomal dominant. The human gene implicated in this disease is ATXN1, which encodes ataxin-1, an RNA-binding protein. SCA1 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. There is one high-scoring fly ortholog of ATXN1, Dmel\Atx-1, for which RNAi targeting constructs and an allele caused by insertional mutagenesis have been generated. Dmel\Atx-1 is orthologous to a second human gene, ATXN1L.
Multiple UAS constructs of the human Hsap\ATXN1 gene have been introduced into flies, including wild-type ATXN1 and ATXN1 genes with expanded (CAG)n repeats. Expression of the Hsap\ATXN1 gene with the pathogenic polyQ expansion in neural tissues results in neurodegenerative phenotypes.
Variant(s) implicated in human disease tested (as transgenic human gene, ATXN1): Q197_Q208 (CAG)n EXPANSION.
Animals homozygous for an insertion in the 3' UTR of the Dmel\Atx-1 gene are viable and fertile. Overexpression of Atx-1 induces degeneration phenotypes in the eye, and visible phenotypes in the wing and bristles. Several physical and genetic interactions have been described for Dmel\Atx-1; see below and in the gene report for Atx-1.
Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).
[updated Mar. 2017 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 1; SCA1](https://omim.org/entry/164400)
[ATAXIN 1; ATXN1](https://omim.org/entry/601556)
Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late adult onset have been reported. Those with onset over age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy. [From GeneReviews, Spinocerebellar Ataxia Type 1, pubmed:20301363 2015.12.14]
Symptoms of SCA1 usually begin in the third or fourth decade of life, most often around age 30. In addition to cerebellar signs, there are upper motor neuron signs and extensor plantar responses. Involuntary choreiform movements may occur (Menzel (1890), Waggoner et al. (1938), and Destunis (1944)). Clinical and pathologic pictures in the disorder are variable. Symptoms vary from those of spinocerebellar ataxia to spastic paraplegia. Identification as a form of OPCA (olivopontocerebellar atrophy) was based on the presence of the major pathology in the inferior olivary nucleus and cerebellum with variable pontine involvement. The spinal cord shows variable loss of anterior motor horn cells and changes in the spinocerebellar tracts and posterior funiculus. Involvement of cranial nerves IX, X and XII is another distinguishing feature (Schut (1950), Schut and Haymaker (1951)). In addition to ataxia, affected persons show lower bulbar palsies, hyperreflexia, scanning and explosive speech, incoordination, and, in some, slow motor-nerve conduction. Neuropathologic findings include atrophy of the cerebellum, pons and olives, degeneration of lower cranial nerve nuclei, and atrophy of the dorsal columns and spinocerebellar tracts. Deep tendon reflexes are increased and the Babinski sign is present (Nino et al., 1980, pubmed:7188630). Neuropathologic features of SCA1 are distinct from those of SCA2 and SCA3 in that brains in SCA1 show almost no neuronal loss from the pars compacta of the substantia nigra or in the locus ceruleus, whereas there is severe atrophy of the dentatorubral pathways. Both SCA1 and SCA2 show severe loss of Purkinje cell and degeneration of the olivocerebellar pathways, which is not seen in SCA3. All 3 disorders share severe atrophy of the nucleus pontis, sparing of the retina and optic nerve, and marked atrophy of Clarke columns and the spinocerebellar tracts. Argyrophilic glial inclusions have not been reported in any of these disorders (Robitaille et al., 1995, pubmed:8615077). [From OMIM:164400, 2015.12.14]
This form of autosomal dominant spinocerebellar ataxia, SCA1, is caused by an expanded (CAG)n trinucleotide repeat in ATXN1, the gene encoding ataxin-1. [From OMIM:164400, 2015.12.14] \
Large nuclear inclusions of ataxin-1 are observed in brain neurons of patients with SCA1 and in mice transgenic for a mutant ATXN1 allele containing 82 glutamines. There is colocalization of the 20S proteasome (see OMIM:602175) and chaperone HSJ2 (OMIM:602837), a member of the Hsp40 family, with these inclusions. In these nuclear inclusions, there was also faint staining for Hsc70 (HSPA8; OMIM:600816), a member of the Hsp70 chaperone family (Cummings et al. (1998, pubmed:9620770). In a mouse model, the majority of wildtype and expanded Atxn1, isolated from soluble protein complexes from mouse cerebellum, assembles into large stable complexes containing the transcriptional repressor Capicua (CIC; OMIM:612082). Atxn1 directly bound Cic and modulated Cic repressor activity in Drosophila and mammalian cells, and its loss decreased the steady state level of Cic (Lam et al., 2006, pubmed:17190598). Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded Atxn1, substantially reduced the association of mutant Atxn1 with Cic in vivo (Emamian et al., 2003, pubmed:12741986). These observations suggest that the neuropathology of SCA1, caused by expansion of the ATXN1 polyglutamine tract, depends on native, not novel, protein interactions (Lam et al., 2006, pubmed:17190598). The expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favors the formation of a particular protein complex containing RBM17 (OMIM:606935), contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism (Lim et al., 2008, pubmed:18337722). [From OMIM:164400 and OMIM:601556, 2015.12.14]
ATXN1 binds RNA, associates with large protein complexes, and interacts with a vast network of proteins. ATXN1 is thought to be involved in transcriptional repression and to regulate Notch- (see OMIM:190198) and Capicua- (CIC; OMIM:612082) controlled developmental processes (summary by Bergeron et al., 2013, pubmed:23760502). The majority of CIC associates with ATXN1 in vivo and that ATXN1 binds CIC through an 8-amino-acid sequence conserved across species (Lam et al., 2006, pubmed:17190598). [From OMIM:601556, 2015.12.14]
Many to one: 2 human to 1 Drosophila (See DIOPT, link below).
Ortholog of human ATXN1 and ATXN1L (2 Drosophila to 1 human).
Dmel\Atx-1 shares 38% identity and 58% similarity with human ATXN1, and 35% identity and 51% similarity to human ATXN1L.