SCA1 is present in individuals where the region on at least one copy of chromosome 6 contains 39 or more continuous repeats of glutamine in which more repeats are correlated to earlier onset and faster progression. Histidine interruptions in the polygluatamine tract can mitigate or prevent SCA1.SCA1 is known to exhibit genetic anticipation, where one generation with the disease may exhibit earlier onset and faster progression than the previous generation. This is typically caused by expansions in the polyglutamine tract between generations and is more common in cases of patrilineal inheritance. This non-Mendelian inheritance is similar to that observed in Huntingtons disease and is believed to be caused by differences in various mechanisms in gamete production between the sexes that result in increased mosaicism in the male germline. DNA with CAG repeats are prone to forming secondary structures, including hairpin loops and R-loops, which can result in mutations and mosaicism if DNA repair mechanisms fail. These secondary structures cause somatic mosaicism by lagging DNA polymerase in Okazaki fragments and by disrupting DNA mismatch repair, base excision repair, nucleotide excision repair and double strand break repair mechanisms. The mechanism for germline expansions is not well understood, but it is believed that only mismatch repair pathways effect germline instability and the MSH2 repair protein has been linked to expansions in male gametes in mice models. Pathophysiology
Normal ataxin 1 is intimately involved in a number of signaling pathways, in protein ubiquitination, RNA metabolism, in transcription regulation, protein transformation, and protein stabilization.
Cell replacement therapies
One treatment option being investigated is stem cell therapy, which attempts to replace dead tissue by transplanting stem cells into affected region and either stimulating them to differentiate into the desired cell types or allowing them to stimulate endogenous regenerative mechanisms. These techniques are of interest to researchers as a possible treatment for neurodegenerative diseases, but currently are of limited success in animal models, and in in-vitro cell culture studies. The ability for grafted cells to integrate into the desired tissue and adjust for the unique pathologies of different neurodegenerative disorders can be a severe limitation on the development of stem cell based treatments. Further, the tissues in the brain often rely on intricate and complicated arrangements of neurons; regions of the brain that do not require precision in these patterns to function, like the striatum affected by Parkinsons disease which uses paracrine signaling, tend to have better results in stem cell therapies than systems that require precision, like the cerebellum and pons. Stem cell therapies can be especially difficult in replacing Purkinje neuron loss as unaffected granule cells can prevent axons reaching the deep cerebellar nuclei with which Purkinje cells interface. Despite these difficulties, grafted neural precursor cells have been shown to be viable and to successfully migrate into desired location in SCA1 transgenic mice models and mesenchymal stem cells have been shown to mitigate loss of dendritic arborization SCA1 mice.