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The pathobiology of perturbed mutant huntingtin protein-protein interactions in Huntington's disease

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Item Type:Review
Title:The pathobiology of perturbed mutant huntingtin protein-protein interactions in Huntington's disease
Creators Name:Wanker, E.E. and Ast, A. and Schindler, F. and Trepte, P. and Schnoegl, S.
Abstract:Mutations are at the root of many human diseases. Still, we largely do not exactly understand how they trigger pathogenesis. One, more recent, hypothesis has been that they comprehensively perturb protein-protein interaction (PPI) networks and significantly alter key biological processes. Under this premise, many rare genetic disorders with Mendelian inheritance, like e.g. Huntington's disease and several spinocerebellar ataxias, are likely to be caused by complex genotype-phenotype relationships involving abnormal PPIs. These altered PPI networks and their effects on cellular pathways are poorly understood at the molecular level. In this review, we focus on PPIs that are perturbed by the expanded pathogenic polyglutamine tract in huntingtin (HTT), the protein which, in its mutated form, leads to the autosomal dominant, neurodegenerative Huntington's disease. One aspect of perturbed mutant HTT interactions is the formation of abnormal protein species such as fibrils or large neuronal inclusions due to homotypic and heterotypic aberrant molecular interactions. This review focuses on abnormal PPIs that are associated with the assembly of mutant HTT aggregates in cells and their potential relevance in disease. Furthermore, the mechanisms and pathobiological processes that may contribute to phenotype development, neuronal dysfunction and toxicity in HD brains are also discussed.
Keywords:Huntingtin, Huntington's Disease, Interactomics, Pathobiology, Perturbed Protein-Protein Interactions, Protein Aggregation, Animals
Source:Journal of Neurochemistry
Page Range:507-519
Date:November 2019
Official Publication:https://doi.org/10.1111/jnc.14853
PubMed:View item in PubMed

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