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. Among other interactions, it forms a transcription complex with Retinoid-related Orphan nuclear-receptor transcription factor α (RORα) following interactions with an activator, Histone acetyltransferase KAT5, sometimes referred to as TIP60, and it is in the signaling mediated by metabotropic glutamate receptor 1 (mGluR1). Resonant Recognition Modeling of the ataxin 1 protein has shown possible binding sites for growth factor independent transcription repressor 1 (Gfi-1). The predictions of this computational model reveal an interaction that could play a role in<unk>  pathology, because the Gfi-1 protein is known to cause selective degradation of Purkinje cells. It is the extensive involvement of ataxin 1 in many different functions that make understanding the biochemical pathophysiology of its mutant form difficult to identify and understand. The mechanism by which expanded CAG repeat regions in ataxin 1 cause neuronal degeneration is unclear. It was historically believed to be caused by aggregation and deposition of the affected protein similar to other polyglutamine expansion diseases, however rodent model studies have shown significantly later formation of nuclear inclusions of mutant proteins in cerebellum and spinal cord neurons than in cortical and hippocampal neurons, which typically show only mild degeneration in<unk>  persons, suggesting a more complicated mechanism. Ataxin-null mice are shown to exhibit reduced motor and spatial learning, suggesting ataxin 1 plays a role in synaptic plasticity and interactions between the motor neurons and the hippocampus. However mice lacking both copies of ataxin 1 do not develop progressive neurological symptoms or show signs of atrophy, suggesting that toxicity of the mutated protein, not loss of function, is the main mechanism for<unk>  pathology. A comparison of mRNA between ataxin null mice and mice with ataxin1154Q/+ shows that there are common changes in gene expression, including upregulation of genes known to be repressed by an ataxin 1/CIC complex. This suggest that, while not the primary mechanism, a loss of ataxin 1 function contributes to the pathogenesis of<unk> . While the ataxin 1/CIC complex losses some of its regulatory function with expanded ataxin 1, CIC knockout mice do not show degeneration, suggesting interactions between ataxin 1 and CIC mediate most of the toxic effects. Mutant ataxin-1 also known to alter the neural circuitry of the developing cerebellum, which may lead to later vulnerability of Purkinje cells and suggests the existence of non-cell autonomous toxicity. The various interactions of ataxin 1 lead to many possible factors that can exasperate or moderate toxicity of its mutant form. Wild type ataxin 1 is quickly degraded in the cytoplasm, but can be stabilized by phosphorylation and 14-3-3 binding as needed by the cell.<unk>  positive mice haplodeficient in 14-3-3ε+/- were shown not to exhibit cerebellar degeneration but still exhibited lethal bulbar degeneration, suggesting that cerebellar atrophy may be related to increased stability of the expanded ataxin 1 protein and that there may be different pathogenic mechanisms for different regions of the brain. The site of phosphorylation is the serine at the 776th residue in ataxin 1. Similar to those that lack 14-3-3 proteins, mice with this residue replaced with alanine do not exhibit cerebellar syndrome. Similarly, removal of the AXH domain from ataxin 1 prevents aberrant interactions with growth factor independent transcription repressor 1 that leads to GFI1 degradation in the proteasome. The expanded polyglutamine region results in increased affinity of the ataxin 1 AXH domain for certain transcription factors, and this effect is believed to play a significant role in ataxin 1 toxicity. Another protein shown to have significant interactions with ataxin 1 is the leucine-rich acidic nuclear protein or LANP. Its function is unknown, but it is predominately expressed in the same neurons as ataxin 1 and has been shown to localize in the nuclei of these neurons at the same substructures as ataxin 1. LANP only interacts with the polyglutamine region of ataxin 1, and its interactions are stronger as the number of glutamine residues increases, so the two proteins are likely vital to each other's functions in neurons and LANP may also facilitate pathology of mutant ataxin 1 proteins. Ataxin 1 like, also called Brother of Ataxin 1 or Boat, has significant interactions with ataxin-1 and many associated proteins, like N-CoR. Ataxin 1 like has reduced expression in transgenic mice models and has been shown to moderate cytotoxicity of ataxin-1. Toxicity from the mutated protein causes degradation in neural tissues. This includes loss of dendritic aborization, or branching, early in disease progression and eventual atrophy of brain tissues in later stages.<unk>  causes moderate degradation of a variety of tissues, including both hemispheres of the cerebellum, the cerebellar vermis, the pons, and the brain stem. It also causes mild atrophy in cerebral cortical tissue. A recent study also found significant atrophy of the spinal cord and flattening of the posterior column and found a correlation between cord area, CAG repeats, and SARA scores in<unk> . Central nervous system tissues, unlike that of bone, muscle, or skin, lacks mechanisms for endogenously generating and differentiating new cells and for restoring long distance patterns and connections as they are lost, so as degeneration progresses the losses are permanent.
Spinocerebellar ataxia type 1
Spinocerebellar ataxia type 6
Spinocerebellar ataxia type-13
Autosomal recessive cerebellar ataxia type 1
Metachromatic leukodystrophy
Benign hereditary chorea
Stratton Parker syndrome
Friedreich's ataxia