Disease relevance of ATXN2

• The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia [1].
• 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].
• Spinocerebellar ataxia type 2 is an inherited neurodegenerative disorder that is caused by an expanded trinucleotide repeat in the SCA2 gene, encoding a polyglutamine stretch in the gene product ataxin-2 [2].
• Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer's disease and spinocerebellar ataxia 2 [3].
• The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation [4].
• [(123)I]FP-CIT SPECT and [(11)C]raclopride PET provide a useful way to evaluate the degree of nigrostriatal dopaminergic damage in SCA2-related parkinsonism and gene carriers [5].

Psychiatry related information on ATXN2

• Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India [6].
• To identify the prevalence and determinants of restless legs syndrome (RLS) in spinocerebellar ataxia (SCA) we studied 58 patients with a molecular diagnosis of SCA1, SCA2 and SCA3 [7].
• Cognitive function was studied in 17 patients with genetically confirmed SCA2 and 15 age- and IQ- matched controls using a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive functions [8].
• Disturbance of rapid eye movement sleep in spinocerebellar ataxia type 2 [9].
• Other disease-related factors (age at onset, genotypic variety) could play a critical role: among these, the size of the expanded CAG repeats is significantly related to a decline of verbal intelligence and short-term memory in SCA2 patients [10].

High impact information on ATXN2

• Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human [11].
• We examined whether similar features define spinocerebellar ataxia type 2 (SCA2) pathogenesis using cultured cells, human brains and transgenic mouse lines [11].
• One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2) [12].
• The SCA2 cDNA is predicted to code for 1,313 amino acids-with the CAG repeats coding for a polyglutamine tract [13].
• Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 [14].

Chemical compound and disease context of ATXN2

• OBJECTIVE: To describe the clinical and molecular genetic analysis of a large family of northern Chinese descent with a mutation at the SCA2 locus causing carbidopa-levodopa-responsive parkinsonism [15].
• SCA2 may present as levodopa-responsive parkinsonism [16].
• Suppression of myoclonus in SCA2 by piracetam [17].

Biological context of ATXN2

• No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed [1].
• The SCA2 gene product, ataxin-2, is a basic protein with two domains (Sm1 and Sm2) implicated in RNA splicing and protein interaction [3].
• A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes [4].
• Spinocerebellar ataxia type 2 (SCA2), one of the hereditary human neurodegenerative disorders, is caused by the expansion of the CAG tandem repeats in the translated sequence of the SCA2 gene [18].
• The most common underlying loci for olivopontocerebellar atrophy (OPCA) are SCA-1 and SCA-2, although other genotypes may be added in the future [19].

Anatomical context of ATXN2

• By immunocfluorescent staining, A2BP1 and ataxin-2 were both localized to the trans -Golgi network [20].
• Western blot analysis of subcellular fractions indicated enrichment of A2BP1 in the same fractions as ataxin-2 [20].
• Immunocytochemistry showed that A2BP1 was expressed in the cytoplasm of Purkinje cells and dentate neurons in a pattern similar to that seen for ataxin-2 labeling [20].
• Among the cases of OPCA, those identified as SCA-2 showed the most severe overall synaptic destruction in cerebellum and brain stem [21].
• Two sisters presented with olivopontocerebellar atrophy, neuronal loss in the substantia nigra, intranuclear ubiquitin-, ataxin-2-positive inclusions in neurons, and severe demyelination and axon loss of the cerebral white matter with no accompanying inflammatory pathology [22].

Associations of ATXN2 with chemical compounds

• The ability of polyglutamine tracts to interact with each other, as well as the presence of intra-nuclear inclusions in other polyglutamine disorders, led us to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset [23].
• A number of peaks in the expanded allele on polyacrylamide gel electrophoresis showed the presence of cell mosaicism in SCA2 as well [24].
• Using the 1C2 antibody which specifically recognizes large polyglutamine tracts, particularly those that are expanded, we recently reported the detection of proteins with pathological glutamine expansions in lymphoblasts from another form of ADCA type I, SCA2, as well as from patients presenting with the distinct phenotype of ADCA type II [25].
• Spinocerebellar ataxia type 2 (SCA2) has not previously been described as causing a typical dopamine-responsive asymmetric PD phenotype [15].
• The parkin mutations and SCA2 were the most frequent genetic causes in our series with Chinese ethnicity [26].

Physical interactions of ATXN2

• Using the yeast two-hybrid system, we identified a novel protein, A2BP1 (ataxin-2 binding protein 1) which binds to the C-terminus of ataxin-2 [20].
• Here, we substantiate a function of ataxin-2 in such pathways by demonstrating that ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6, a component of P-bodies and stress granules, representing cellular structures of mRNA triage [27].
• Parkin interacted with the N-terminal half of normal and mutant ataxin-2, and ubiquitinated the full-length form of both wild-type and mutant ataxin-2 [28].

Regulatory relationships of ATXN2

• Parkin reduced abnormalities in Golgi morphology induced by mutant ataxin-2 and decreased ataxin-2 induced cytotoxicity [28].

Other interactions of ATXN2

• This result implicates RAI1 as a possible contributor to SCA2 neurodegeneration and raises the possibility that other CAG-containing proteins may play a role in the pathogenesis of other polyglutamine disorders [23].
• Ataxin-2 and A2RP are proteins highly conserved in evolution with orthologs in mouse, cattle, pig, frog, and plants [29].
• In this study, we have determined the SCA1 and SCA2 genotypes in a Polish population and found significant differences in allele spectra and frequencies from those reported for other populations [30].
• While the neurons of the basis pontis do not properly belong to this module, pontine atrophy is an important additional lesion in SCA-1, SCA-2, and SCA-7 [31].
• We show here that the properties of the CAA interruptions are major determinants of the CAG repeat folding in the normal SCA2 transcripts [18].

Analytical, diagnostic and therapeutic context of ATXN2

• Immunofluorescence studies revealed that ATX2 and PABP co-localize in mammalian cells, remarkably, even under conditions in which PABP accumulates in distinct cytoplasmic foci representing sites of mRNA triage [32].
• A simple non-radioactive PCR for rapid detection of the expanded SCA2 alleles via agarose gel electrophoresis was also employed [33].
• MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2 [34].
• 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 [35].
• The pedigree reported here will be valuable in the identification and cloning of a gene for hereditary ataxia, designated "SCA2" at the Eleventh International Workshop on Human Gene Mapping [36].

References