Human Disease Model Report: Machado-Joseph disease (SCA3)
This report describes Machado-Joseph disease (MJD), which is a subtype of spinocerebellar ataxia; MJD is inherited as an autosomal dominant. The human gene implicated in this disease is ATXN3, which encodes ataxin 3, a component of the ubiquitin proteasome system. MJD 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. No ortholog of ATXN3 has been identified in flies.
Multiple UAS constructs of the human Hsap\ATXN3 gene have been introduced into flies, including wild-type ATXN3, ATXN3 genes with expanded (CAG)n repeats, and ATXN3 genes carrying mutational lesions. Expression of the truncated Hsap\ATXN3 protein with the pathogenic polyQ expansion in neural tissues results in neurodegenerative phenotypes. Variant(s) implicated in human disease tested (as transgenic human gene, ATXN3): Q296_Q305 (CAG)n EXPANSION; most experiments have used a truncated protein with the polyQ expansion.
When expressed in transgenic flies, the human Hsap\ATXN3 protein has been shown to interact with the fly ortholog of VCP (TER94); VCP is implicated in amyotrophic lateral sclerosis 14 (see FBhh0000021). This interaction is dependent upon the identified VCP-binding site in the human ATXN3 protein.
Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).
[updated Dec. 2018 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]
[MACHADO-JOSEPH DISEASE; MJD](https://omim.org/entry/109150)
[ATAXIN 3; ATXN3](https://omim.org/entry/607047)
Machado-Joseph disease, named for affected families of Azorean extraction, is an autosomal dominant progressive neurologic disorder characterized principally by ataxia, spasticity, and ocular movement abnormalities. Although independently described as a seemingly separate disorder, spinocerebellar ataxia-3 is now known to be the same as Machado-Joseph disease. [From OMIM:109150, 2015.12.14]
This form of autosomal dominant spinocerebellar ataxia, Machado-Joseph disease (MJD), also known as spinocerebellar ataxia-3 (SCA3), is caused by a (CAG)n trinucleotide repeat expansion encoding glutamine repeats in ATXN-3, the gene encoding ataxin-3. [From OMIM:109150, 2015.10.29]
ATXN3 with a polyglutamine sequence in the pathologic range accumulates in ubiquitinated intranuclear inclusions selectively in neurons of affected brain regions. In vitro evidence supports a model of disease in which an expanded polyglutamine-containing fragment recruits full-length protein into insoluble aggregates (Paulson et al., 1997, pubmed:9292723). [From OMIM:607047, 2015.12.14]
ATXN3 has deubiquitinase activity and appears to be a component of the ubiquitin proteasome system. It may also have roles in transcriptional regulation and neuroprotection (summary by Haacke et al., 2006, pubmed:16407371). [From OMIM:607047, 2015.10.29]
No gene orthologous to human ATXN3 in Drosophila (DIOPT).
