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General Information
Name
Machado-Joseph disease (SCA3)
FlyBase ID
FBhh0000063
Overview

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]

Disease Summary Information
Parent Disease Summary: spinocerebellar ataxia, autosomal dominant
Symptoms and phenotype

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]

Specific Disease Summary: Machado-Joseph disease (SCA3)
OMIM report

[MACHADO-JOSEPH DISEASE; MJD](https://omim.org/entry/109150)

Human gene(s) implicated

[ATAXIN 3; ATXN3](https://omim.org/entry/607047)

Symptoms and phenotype

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]

Genetics

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]

Cellular phenotype and pathology

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]

Molecular information

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]

External links
Disease synonyms
MJD
spinocerebellar ataxia 3
SCA3
spinocerebellar atrophy III
Azorean neurologic disease
spinopontine atrophy
nigrospinodentatal degeneration
Machado-Joseph disease; MJD
Machado disease
Joseph disease
MJD/SCA3
spinocerebellar ataxia type 3
Machado-Joseph disease
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

No gene orthologous to human ATXN3 in Drosophila (DIOPT).

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (0)
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (3 groups)
    protein-protein
    Interacting group
    Assay
    References
    anti tag coimmunoprecipitation, anti tag western blot
    pull down, western blot
    pull down, western blot, anti tag coimmunoprecipitation
    Alleles Reported to Model Human Disease (Disease Ontology) (18 alleles)
    Models Based on Experimental Evidence ( 15 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 14 )
    Allele
    Disease
    Interaction
    References
    is ameliorated by Rac1UAS.cLa
    is exacerbated by Rac1V12.UAS
    is exacerbated by CG7130GD2776
    is ameliorated by effHM05268
    is exacerbated by Atg12JF02704
    is exacerbated by Atg8aHMS01328
    is exacerbated by Atg7GD11671
    is exacerbated by sip3GD3145
    is ameliorated by DnaJ-1UAS.cKa
    is ameliorated by CG9934JF02691
    is ameliorated by parkHMS01651
    is exacerbated by STUB1HMS00986
    is ameliorated by embE2-1A
    is ameliorated by dbrEP9
    is ameliorated by dbrEP456
    is ameliorated by orb2B8-S
    is ameliorated by Faf2E659
    is ameliorated by wechE546
    is ameliorated by mrjE1050
    is exacerbated by Cdk5GD13840
    is NOT exacerbated by cdmJF01428
    is ameliorated by embEY08770
    is exacerbated by embJF01311
    is ameliorated by cdmGS17666
    is exacerbated by Cul1GD9650
    is exacerbated by Cul1NIG.1877R
    is exacerbated by FipoQKK108266
    is ameliorated by Atx2HMS02726
    is exacerbated by UckGD229
    is exacerbated by TbpsI10
    is exacerbated by TbpUAS.cHa
    is ameliorated by nejEP1410
    is exacerbated by Khc9
    is exacerbated by loqsf00791
    is ameliorated by mir-banB90.1
    is exacerbated by U2af50XR15
    is exacerbated by mblUAS.cLa
    is ameliorated by Rpn11DANC
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    References (116)