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      Kaleidoscopic protein–protein interactions in the life and death of ataxin-1: new strategies against protein aggregation

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          Highlights

          • Ataxin-1 (Atx1) is the protein responsible for spinocerebellar ataxia type 1 (SCA1).

          • Normal function and anomalous aggregation are competing pathways.

          • Protein–protein interactions protect Atx1 from aggregation and misfolding.

          • This knowledge can be exploited in drug development.

          Abstract

          Understanding how proteins protect themselves from aberrant aggregation is of primary interest for understanding basic biology, protein biochemistry, and human disease. We discuss the paradigmatic example of ataxin-1 (Atx1), the protein responsible for neurodegenerative spinocerebellar ataxia type 1 (SCA1). This disease is part of the increasing family of pathologies caused by protein aggregation and misfolding. We discuss the importance of protein–protein interactions not only in the nonpathological function of Atx1 but also in protecting the protein from aggregation and misfolding. The lessons learned from Atx1 may lead to a more general understanding of the cell's protective strategies against aggregation. The obtained knowledge may suggest a new perspective for designing specific therapeutic strategies for the cure of misfolding diseases.

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          Most cited references47

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          EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers.

          The accumulation of beta-sheet-rich amyloid fibrils or aggregates is a complex, multistep process that is associated with cellular toxicity in a number of human protein misfolding disorders, including Parkinson's and Alzheimer's diseases. It involves the formation of various transient and intransient, on- and off-pathway aggregate species, whose structure, size and cellular toxicity are largely unclear. Here we demonstrate redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers. The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.
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            A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.

            Many human inherited neurodegenerative disorders are characterized by loss of balance due to cerebellar Purkinje cell (PC) degeneration. Although the disease-causing mutations have been identified for a number of these disorders, the normal functions of the proteins involved remain, in many cases, unknown. To gain insight into the function of proteins involved in PC degeneration, we developed an interaction network for 54 proteins involved in 23 inherited ataxias and expanded the network by incorporating literature-curated and evolutionarily conserved interactions. We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen; of 75 pairs tested, 83% of the interactions were verified in mammalian cells. Many ataxia-causing proteins share interacting partners, a subset of which have been found to modify neurodegeneration in animal models. This interactome thus provides a tool for understanding pathogenic mechanisms common for this class of neurodegenerative disorders and for identifying candidate genes for inherited ataxias.
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              Identification of genes that modify ataxin-1-induced neurodegeneration.

              A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
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                Author and article information

                Contributors
                Journal
                Trends Neurosci
                Trends Neurosci
                Trends in Neurosciences
                Elsevier Applied Science Publishing
                0166-2236
                1878-108X
                1 April 2014
                April 2014
                : 37
                : 4
                : 211-218
                Affiliations
                [1 ]National Institute for Medical Research (NIMR), Medical Research Council (MRC), The Ridgeway, London NW7 1AA, UK
                [2 ]Department of Clinical Neurosciences, King's College London, Denmark Hill Campus, London, UK
                Article
                S0166-2236(14)00017-4
                10.1016/j.tins.2014.02.003
                3988977
                24636457
                7d8d315f-44ce-41f3-9e67-1156f8f23d86
                © 2014 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

                History
                Categories
                Review

                Neurosciences
                misfolding diseases,polyglutamine,protein aggregation,protein–protein interactions

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