Disease relevance of ATXN3

• In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia [1].
• Both wild-type Atx-3 and the otherwise unrelated Ub-binding protein p62/Sequestosome-1 have been shown to be sequestered into aggregates in affected neurons in several neurodegenerative diseases, but the mechanism for this recruitment has remained unclear [2].
• The autosomal dominant ataxias such as olivopontocerebellar atrophy (OPCA), familial cortical cerebellar atrophy (FCCA), and Machado-Joseph disease (MJD) have been renamed the spinocerebellar ataxias (SCA) [3].
• The neuropathological phenotype included 18 cases of olivopontocerebellar atrophy (OPCA), 14 cases of familial cortical cerebellar atrophy (FCCA), 4 cases of Machado-Joseph disease (MJD), and 21 cases of Friedreich's ataxia (FA) [4].
• In this study, human SK-N-SH neuroblastoma cells stably transfected with full-length MJD with 78 CAG repeats were established [5].

Psychiatry related information on ATXN3

• The diffuse nuclear labeling was also detected in MJD, Huntington's disease, and spinal and bulbar muscular atrophy, suggesting that this nuclear pathology may be a characteristic feature and may exert certain influence on certain nuclear functions of many neurons in the CAG repeat diseases [6].
• These include Alzheimer's disease, Parkinson's disease, tauopathies, and polyglutamine expansion diseases [e.g., Huntington's disease; and various spinocerebellar ataxias (SCAs), like SCA3] [7].
• These findings indicate that the orexin/ataxin-3 transgenic rat could provide a useful model of human narcolepsy [8].
• Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome [9]?
• PARTICIPANTS: Sixteen genetically confirmed MJD patients able to complete neuropsychological tests and 20 control subjects matched to patients by age and education [10].

High impact information on ATXN3

• Spinocerebellar ataxia type 3 (SCA3/MJD) is one of at least eight human neurodegenerative diseases caused by glutamine-repeat expansion [11].
• We have recreated glutamine-repeat disease in Drosophila using a segment of the SCA3/MJD protein [11].
• Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo [12].
• Recently, we identified a novel gene, MJD1, which contains an expanded CAG triplet repeat in Machado-Joseph disease [12].
• Here we report the induction of apoptosis in cultured cells expressing a portion of the MJD1 gene that includes the expanded CAG repeats [12].

Chemical compound and disease context of ATXN3

• Spinocerebellar ataxia type 3 is a human neurodegenerative disease resulting from polyglutamine tract expansion [13].
• We observed a parkinsonian variant of SCA3 in which parkinsonism was present in the beginning of the disease and responded well to levodopa therapy, leading to diagnostic confusion [14].
• The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than ataxia [15].
• Consistently, proteolytic cleavage of full-length, pathogenic AT3 initiates the formation of sodium dodecylsulfate-resistant aggregates in neuroblastoma cells [16].
• Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment [17].

Biological context of ATXN3

• Here we report the finding of ataxin-3 (Atx-3), whose mutation is implicated in the neurodegenerative disease spinocerebellar ataxia type 3, in a bioinformatics search of the human genome for components of the Ub system [2].
• The mutant ataxin-3 forms intranuclear inclusions in cultured cells as well as in diseased human brain and also causes cell death in transfected cells [18].
• Furthermore, we confirmed that ataxin-3 interacts with the -ubiquitin-like domain at the N-terminus of the HHR23 proteins, which is important for nucleotide excision repair; however, ataxin-3 does not interact with -ubiquitin, implying that ataxin-3 might be functionally associated with the HHR23 proteins through this specific interaction [18].
• The defect responsible for SCA3/Machado-Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function [19].
• Down-regulation of heat shock protein 27 in neuronal cells and non-neuronal cells expressing mutant ataxin-3 [5].

Anatomical context of ATXN3

• However, in 293 cells HHR23A is recruited to intranuclear inclusions formed by the mutant ataxin-3 through its interaction with ataxin-3 [18].
• Upon immunocytochemical analysis we detected NI in all of the thalamic nuclei of all of our SCA3 patients [20].
• This lack of correlation may suggest that ataxin-3 immunopositive NI are not immediately decisive for the fate of affected nerve cells but rather represent unspecific and pathognomonic morphological markers of SCA3 [20].
• At the level of the spinal cord, synaptic loss in the dorsal nuclei of Clarke characterized FA and MJD/SCA-3 [4].
• In SCA-3, abnormal ataxin-3 is aggregated in neuronal nuclei, and in SCA-6, a mutated alpha1A-calcium channel protein is the likely cause of abnormal calcium channel function in Purkinje cells and in the death of these neurons [3].

Associations of ATXN3 with chemical compounds

• In this article, we show that functional Ub-binding motifs in Atx-3 and p62 proteins are required for the localization of both proteins into aggregates in a cell-based assay that recapitulates several features of polyglutamine disease [2].
• Spinocerebellar Ataxia Type 3 (SCA3): Thalamic Neurodegeneration Occurs Independently from Thalamic Ataxin-3 Immunopositive Neuronal Intranuclear Inclusions [20].
• Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3 [21].
• The lesion of Purkinje cells and their processes in the molecular layer associated with altered glutamate transport may be important in DRPLA, while the significance of the abnormalities observed in some MJD cases, which might be related to apoptotic mechanism, remains unclear [22].
• An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis [23].

Physical interactions of ATXN3

• These differences in NI formation reflect specific protein interactions normally undertaken by ataxin-3, as both normal and mutant full-length ataxin-3 co-immunoprecipitate with CBP and sediment on density gradients as macromolecular complexes [24].

Co-localisations of ATXN3

• Cellular studies show that endogenous AT3 colocalizes with aggresomes and preaggresome particles of the misfolded cystic fibrosis transmembrane regulator (CFTR) mutant CFTRDeltaF508 and associates with histone deacetylase 6 and dynein, proteins required for aggresome formation and transport of misfolded protein [25].

Regulatory relationships of ATXN3

• These data suggest that a normal function of AT3 is to regulate flow through the ERAD pathway by modulating VCP-dependent extraction of proteins from the ER [26].
• A familial factor independent of CAG repeat length influences age at onset of Machado-Joseph disease [27].

Other interactions of ATXN3

• Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics [28].
• A family with Machado-Joseph disease, previously diagnosed as dentatorubral-pallidoluysian atrophy [29].
• Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) was found to harbor SCA3 mutations while none was found to harbor SCA6 mutations [30].
• Our results also showed that unlike SCA 1 and SCA3/MJD, the size distribution of the normal alleles showed few polymorphisms, with the 22 repeat allele accounting for 90.1% [31].
• CONCLUSIONS: Lack of SCA3 and excess of SCA8 are characteristic to the Finnish population [32].

Analytical, diagnostic and therapeutic context of ATXN3

• Most interestingly, from 2D gel electrophoresis analysis, we identified that the expression of heat shock protein 27 (HSP27), known as a suppressor of poly(Q)-mediated cell death, dramatically decreased in SK-N-SH cells stably transfected with full-length mutant MJD [5].
• Triple-labeling immunofluorescence demonstrated colocalization of ataxin-2 and ataxin-3 in NIIs containing expanded polyglutamine, irrespective of the disease examined [33].
• In surface plasmon resonance binding analyses, normal and expanded ataxin-3 display similar submicromolar dissociation constants for tetra-ubiquitin [34].
• Female gender increased the risk of becoming dependent on walking aids or a wheelchair, but it did not influence survival in FRDA, SCA3 and MSA [35].
• Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation were abnormal in almost all SCA1 patients, but only in a minority of SCA2 and SCA3 patients [36].

References