The pathobiology of perturbed mutant huntingtin protein–protein interactions in Huntington's disease. Issue 4 (15th September 2019)

• Record Type: Journal Article
• Authors: Wanker, Erich E.; Ast, Anne; Schindler, Franziska; Trepte, Philipp; Schnoegl, Sigrid
• Other Names: Cookson Mark R. guestEditor.
• Is Part Of: Journal of neurochemistry. Volume 151:Issue 4(2019)
• Page Start: 507
• Page End: 519
• Publication Date: 2019-09-15
• Subjects: huntingtin -- Huntington's disease -- interactomics -- pathobiology -- perturbed protein–protein interactions -- protein aggregation; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14853
• Languages: English
• ISSNs: 0022-3042

Abstract

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 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 as a result of 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 Huntington's disease brains are also discussed. This article is part of the Special Issue "Proteomics" . Abstract : How mutations trigger human diseases is largely unclear. From a network biology perspective, they alter biological processes by disrupting cellular protein–protein interaction (PPI) patterns. Many rare genetic disorders with Mendelian inheritance, like the neurodegenerative Huntington's disease, may be caused by abnormal PPIs and their adverse effects on complex cellular genotype–phenotype relationships. In this review, we focus on abnormal PPIs associated with mutant huntingtin and its assembly into protein aggregates in cells. The mechanisms and pathobiological processes that may contribute to phenotype development, neuronal dysfunction and toxicity in Huntington's disease are also discussed. This article is part of the Special Issue "Proteomics" .