Disease relevance of ATXN1

• SCA1 belongs to a growing group of neurodegenerative disorders caused by expansion of CAG repeats, which encode glutamine [1].
• Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase [2].
• A correlation between clinical severity as assessed with the Inherited Ataxias Clinical Rating Scale (IACRS) and the 50th percentile of the D value in the brainstem and cerebellum histogram (r = 0.69) was observed in patients with SCA1 or SCA2 [3].
• We had previously described the leucine-rich acidic nuclear protein (LANP) as a candidate mediator of toxicity in the polyglutamine disease, spinocerebellar ataxia type 1 (SCA1) [4].
• Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6 [5].
• As LANP interacts with ataxin 1--a protein mutated in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1)--we tested whether ataxin 1 can alter the E4F-LANP interaction [6].

Psychiatry related information on ATXN1

• This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease [7].
• The clinical profile of this family was similar to that of previously described SCA1 and non-SCA1 families, except that dementia was observed in 2 out of 6 patients [8].
• 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 [9].
• CONCLUSION: The characteristics of this family broaden the clinical picture of spinocerebellar ataxia type 17: initial presenile dementia with behavioral symptoms should be added to ataxia, rigidity, and dystonic movements, which are more commonly encountered [10].
• Fourteen patients with spinocerebellar ataxia 1 (SCA1) and 11 controls with similar mean age and IQ estimates were submitted to a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory as well as executive functions [11].

High impact information on ATXN1

• We have discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families [12].
• Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8 [13].
• The neurodegenerative disease Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine expansion disorder characterized by the death of Purkinje neurons in the brain [14].
• In this issue, propose that toxicity of the polyglutamine protein Ataxin-1 may not be due to abberant protein interactions mediated by the polyglutamine expansion [15].
• We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance [13].

Chemical compound and disease context of ATXN1

• Spinocerebellar ataxia type1 (SCA1) is one of several neurodegenerative disorders caused by expansions of translated CAG trinucleotide repeats which code for polyglutamine in the respective proteins [2].
• Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors [16].
• We previously reported markedly reduced (-76%) dopamine (DA) levels in the putamen of seven patients with spinocerebellar ataxia type 1 (SCA1) who had no evidence of nigral cell loss or parkinsonism [17].
• A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia [18].
• In one such disorder, spinocerebellar ataxia (SCA1), it has been reported that certain individuals with expanded polyglutamine repeats in the disease range (Q(12)HQHQ(12)HQHQ(14/15)) but with histidine interruptions were found to be phenotypically normal [19].

Biological context of ATXN1

• Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death [20].
• Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1 [21].
• Possible reduced penetrance of expansion of 44 to 47 CAG/CAA repeats in the TATA-binding protein gene in spinocerebellar ataxia type 17 [22].
• We describe a behavioral benefit of cerebellar grafts in a transgenic model of SCA-1 in which the ataxic phenotype results from expression of an expanded ataxin-1 protein [23].
• One gene is located in the short arm of chromosome 6 (6p22-p23) and causes spinocerebellar ataxia type 1 (SCA1) [24].

Anatomical context of ATXN1

• LANP is expressed predominantly in Purkinje cells, the primary site of pathology in SCA1 [1].
• Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem [25].
• The wild-type protein is detected in both normal and affected individuals; however, a mutant protein which varies in its migration properties according to the size of the CAG repeat is detected in cultured cells and tissues from SCA1 individuals [26].
• Pathological examinations of the transgenic mice revealed loss of Purkinje and granular cells in the cerebellum as well as that of spinal motor neurons, corresponding to the pathology of human SCA1 [27].
• Ataxin-1 is a polyglutamine protein whose expansion causes spinocerebellar ataxia type-1 (SCA1) and triggers the formation of nuclear inclusions (NIs) [28].

Associations of ATXN1 with chemical compounds

• Although the proteins containing these repeats are widely expressed, the neurodegeneration in SCA1 and other polyglutamine diseases selectively involves a few neuronal subtypes [1].
• We developed a fast and efficient screening method based on touchdown multiplex PCR with fluorescent labelled primers for the most common types of SCAs (SCA 1, 2, 3 and 7) [29].
• It is 54% identical to hamster CPP32/SCA-1, a cysteine protease that was earlier shown to cleave SREBPs at a conserved Asp between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain [30].
• Magnetic resonance (MR) techniques enable in vivo measurement of the atrophy of the brainstem and cerebellum in spinocerebellar ataxia type 1 (SCA1) and 2 (SCA2) patients, which is accompanied by a decrease in the concentration of N-acetyl aspartate (NAA) or of the NAA/creatine ratio in the pons and cerebellum [31].
• The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: gabapentin and pregabalin may be of therapeutic benefit [32].

Physical interactions of ATXN1

• As a possible mechanism underlying this phenomenon, we found that mutant ataxin-1 enhances binding of PQBP-1 to the C-terminal domain of RNA polymerase II large subunit (Pol II) [20].
• BACKGROUND: Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by expansion of CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene [22].

Other interactions of ATXN1

• These results suggest that A1Up may link ataxin-1 with the chaperone and ubiquitin-proteasome pathways [33].
• Seven patients with SCA1 (n = 5) or SCA2 (n = 2) had morphologic changes reminiscent of OPCA, but their values were still in the lower normal range and were classified as undefined [3].
• 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% [34].
• Using the yeast two-hybrid system and co-immunoprecipitation experiments, we have found that p80 coilin, coiled body-specific protein, binds to ataxin-1 [35].
• Because the population of this area had seldom moved, the alleles with SCA1 mutations (including alleles with an intermediate CAG repeat number) are assumed to have been present in this area for a long time [36].

Analytical, diagnostic and therapeutic context of ATXN1

• Immunofluorescence studies demonstrate that both LANP and ataxin-1 colocalize in nuclear matrix-associated subnuclear structures [1].
• CHIP promotes ubiquitination of expanded ataxin-1 both in vitro and in cell culture [28].
• Sequence analyses of the repeats in primates revealed shorter polyglutamine stretches in some of the non-human primates at all three loci and marked diversions from the expected polyglutamines in the orang-utan Machado-Joseph gene and in the marmoset spinocerebellar ataxia type 1 gene [37].
• MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2 [38].
• The correlation in SCA1 between clinical severity and quantitative volumetric, diffusion MRI and proton MR spectroscopy findings in the brainstem indicates that these measurements might be employed for longitudinal studies and hopefully as surrogate markers in future pharmacological trials of this condition [31].

References