ATXN1 is conserved across multiple species, including humans, mice, and Drosophila. In humans, ATXN1 is located on the short arm of chromosome 6. The gene contains 9 exons, two of which are protein-coding. There is a CAG repeat in the coding sequence which is longer in humans than other species. This repeat is prone to errors in DNA replication and can vary widely in length between individuals.
The function of Ataxin-1 is not completely understood. It appears to be involved in regulating gene expression based on its location in the nucleus of the cell, its association with promoter regions of several genes, and its interactions with transcriptional regulators and parts of the RNA splicing machinery.
ATXN1 is the gene mutated in spinocerebellar ataxiatype 1, a dominantly-inherited, fatal genetic disease in which neurons in the cerebellum and brain stemdegenerate over the course of years or decades. SCA1 is a trinucleotide repeat disorder caused by expansion of the CAG repeat in ATXN1; this leads to an expanded polyglutamine tract in the protein. This elongation is variable in length, with as few as 6 and as many as 81 repeats reported in humans. Repeats of 39 or more uninterrupted CAG triplets cause disease, and longer repeat tracts are correlated with earlier age of onset and faster progression. How polyglutamine expansion in Ataxin-1 causes neuronal dysfunction and degeneration is still unclear. Disease likely occurs through the combination of several processes.
Aggregation
Mutant Ataxin-1 protein spontaneously misfolds and forms aggregates in cells, much like other disease-associated proteins such as tau, Aβ, and huntingtin. This led to the hypothesis that the aggregates are toxic to neurons, but it has been shown in mice that aggregation is not required for pathogenesis. Other neuronal proteins can modulate the formation of Ataxin-1 aggregates and this in turn may affect aggregate-induced toxicity.
Altered protein-protein interactions
Soluble Ataxin-1 interacts with many other proteins. Polyglutamine expansion in Ataxin-1 can affect these interactions, sometimes causing loss of function and sometimes causing toxic gain of function. This, in turn, could alter the expression of the genes ataxin-1 regulates, leading to disease.
Mutant ataxin1 causes the neurodegenerative disease spinocerebellar ataxia type 1. In a mouse model of SCA1, mutant ataxin1 mediates the reduction or inhibition of the high mobility group box1 protein in neuronmitochondria. HMGB1 is a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. The impairment of HMGB1 function leads to increased mitochondrial DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitates repair of the mitochondrial DNA damage, ameliorates the neuropathology and the motor deficits, and extends the lifespan of these mutant ataxin1 mice.
