So what are the other molecular players, and how do they interact to bring about neurodegeneration? To address these questions, Lim et al. They find that ATXN1 mutation is accompanied by alterations in the cellular levels of at least two distinct ATXN1-containing, disease-associated protein complexes. There are two main types of mutation. In the less common gain-of-function mutations, the protein concerned either acquires new activity or its existing activity is enhanced.
By contrast, in loss-of-function mutations, the activity of the mutated protein is either reduced or abolished. In polyglutamine diseases, because the extra glutamine residues in the mutant protein acquire toxic properties — through impaired protein folding and degradation pathways, altered subcellular localization, abnormal interactions with other cellular proteins and other events — early research focused on target proteins and cellular processes that contribute to a gain of function.
The possibility that loss-of-function effects play a part in these diseases was considered less likely: knock-out mice that do not express a polyglutamine-disease gene, including Atxn1 , do not have the disease symptoms that are observed when these genes are mutated, and nor do humans with deletions of such genes 5 , 6. But, although it is tempting to conclude from these previous studies that loss of function does not have significant consequences, a more likely explanation is that, whereas the normal function of a disease gene is necessary, its loss is not sufficient to cause a polyglutamine disease.
With the exception of spinal and bulbar muscular atrophy 2 , the culprit protein for most polyglutamine disorders was first characterized as of unknown function. For example, it emerged only some time after its discovery that the huntingtin protein, which is mutated in Huntington's disease, is likely to regulate axonal trafficking in neurons, enhance neuron-specific gene transcription by sequestering the transcription-repressor protein REST, and potentially act as an essential scaffolding protein to organize the components of cellular pathways or structures 3 , 7.
With polyglutamine-repeat expansion in the mutant huntingtin, and when this is mimicked experimentally 8 , REST has greater freedom to suppress gene expression; mutant huntingtin might even aid this process. Similar loss-of-function effects are observed after mutation of the ataxin 7 or ataxin 3 genes, which lead to other polyglutamine diseases 1 , 2.
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For spinocerebellar ataxia 1, several studies 1 , 6 implicated both gain-of-function of the mutant ATXN1 and loss-of-function of the normal protein in its pathology. Previous work 1 , 6 also established a disease-associated role for specific domains within ATXN1 other than the polyglutamine repeat; in different polyglutamine diseases, modifications of different protein domains seem to be involved in modulation of disease.
Lim et al.
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They find that the length of a repeated glutamine tract in ATXN1, which in disease expands to 39 repeats or more, influences the distribution of cellular proteins in ATXN1 complexes. When the tract expands, the formation of complexes containing a protein that promotes neurotoxicity, RBM17, is enhanced. The authors also show that, in the mouse brain, RBM17 is highly expressed in Purkinje cells of the cerebellum — the region most affected in spinocerebellar ataxia 1 — and that in a fruitfly model of spinocerebellar ataxia 1, a reduction in RBM17 levels protects these insects from retinal degeneration; increased levels of this protein promote degeneration.
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So the increased formation of ATXN1—RBM17 complexes may represent a gain of function that seems to contribute to the neurodegeneration observed in spinocerebellar ataxia 1. Lim and colleagues further find that when ATXN1 is mutated, the formation of complexes between it and a protein called capicua is reduced. Previously, the authors have shown 6 that high levels of capicua suppress neurotoxicity in flies. So with decreased formation of ATXN1—capicua complexes in the brain of animals with spinocerebellar ataxia 1, the protective effect of capicua might be lost. Mice that do not express normal ATXN1 but carry a single copy of the mutant gene have worse motor skills and shorter lifespans than mice that express the normal gene as well as a copy of the mutant one.
These observations support the authors' proposed mechanism that normal ATXN1 promotes the formation of a protective complex and keeps the formation of a harmful one in check.
Lim and colleagues' data do not directly prove that the redistribution of ATXN1 between RBMcontaining and capicua-containing complexes causes spinocerebellar ataxia 1. Such protein-interaction studies are likely to lead to insights relating to disease mechanisms, although the answers won't always be straightforward. The complexity of such disorders is illustrated by a protein-interaction screen that identified more than protein partners for mutant huntingtin 9. It will be intriguing to determine whether these interacting proteins are expressed in the affected regions of the Huntington-diseased brain and to compare the strength of these interactions and the distinct complexes that may form in tissues expressing the mutant protein with those expressing normal huntingtin, as shown here for ATXN1.
Proving a direct link between protein interactions and disease will be the next challenging step.
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One approach might be to perform experiments similar to those of Lim et al. But causality will require the expression of relevant disease proteins with mutations in specific domains that prevent complex formation, or other mutations that prevent these complexes from forming in vivo. Unlike neurodegenerative diseases with complex genetics, single-gene disorders such as polyglutamine diseases allow researchers to address specific questions relating to the impact of the polyglutamine-repeat expansion on the function of the normal and mutant proteins.
Ultimately, such studies should tease out molecules crucial for the maintenance of protein balance in the brain. The levels of complexes that ATXN1 makes with each of two other cellular proteins, the neurotoxic RBM17 and the neuroprotective capicua, seem to vary depending on whether a neuron expresses normal ATXN1 a or its mutated version b.
Orr, H. Katsuno, M. Li, S. Lim, J. Nature , — Bates, G.
Brain Pathol. Lam, Y.
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