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      Protein Misfolding and Aggregation as a Therapeutic Target for Polyglutamine Diseases

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          Abstract

          The polyglutamine (polyQ) diseases, such as Huntington’s disease and several types of spinocerebellar ataxias, are a group of inherited neurodegenerative diseases that are caused by an abnormal expansion of the polyQ tract in disease-causative proteins. Proteins with an abnormally expanded polyQ stretch undergo a conformational transition to β-sheet rich structure, which assemble into insoluble aggregates with β-sheet rich amyloid fibrillar structures and accumulate as inclusion bodies in neurons, eventually leading to neurodegeneration. Since misfolding and aggregation of the expanded polyQ proteins are the most upstream event in the most common pathogenic cascade of the polyQ diseases, they are proposed to be one of the most ideal targets for development of disease-modifying therapies for polyQ diseases. In this review, we summarize the current understanding of the molecular pathogenic mechanisms of the polyQ diseases, and introduce therapeutic approaches targeting misfolding and aggregation of the expanded polyQ proteins, which are not only effective on a wide spectrum of polyQ diseases, but also broadly correct the functional abnormalities of multiple downstream cellular processes affected in the aggregation process of polyQ proteins. We hope that in the near future, effective therapies are developed, to bring hope to many patients suffering from currently intractable polyQ diseases.

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          Most cited references108

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          Molecular chaperones in protein folding and proteostasis.

          Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
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            Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

            Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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              Heat shock factors: integrators of cell stress, development and lifespan.

              Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes. These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing.
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                Author and article information

                Journal
                Brain Sci
                Brain Sci
                brainsci
                Brain Sciences
                MDPI
                2076-3425
                11 October 2017
                October 2017
                : 7
                : 10
                : 128
                Affiliations
                Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
                Author notes
                [* ]Correspondence: takeuchi@ 123456neurother.med.osaka-u.ac.jp (T.T.); nagai@ 123456neurother.med.osaka-u.ac.jp (Y.N.); Tel.: +81-6-6879-3564 (T.T. & Y.N.)
                Article
                brainsci-07-00128
                10.3390/brainsci7100128
                5664055
                29019918
                a0e2e3a5-bd27-4b34-9893-bda6db20ec63
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 August 2017
                : 10 October 2017
                Categories
                Review

                polyglutamine diseases,huntington’s disease,conformational change,aggregation,misfolding,β-sheet monomer,therapeutic target,qbp1,molecular chaperone

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