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

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

Publication date: Aug 16, 2019

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. This article is protected by copyright. All rights reserved.

Wanker, E.E., Ast, A., Schindler, F., Trepte, P., and Schnoegl, S. The pathobiology of perturbed mutant huntingtin protein-protein interactions in Huntington’s disease. 06638. 2019 J Neurochem.

Concepts Keywords
Assembly Huntingtin-associated protein 1
Autosomal Dominant Genotype
Fibrils Interactome
Genetic Disorders Neurodegeneration
Genotype Spinocerebellar ataxia
Huntingtin Protein–protein interaction
Huntingtin Protein Huntingtin
Huntington Huntington’s disease
Mendelian Inheritance Autosomal dominant disorders
Mutant Branches of biology
Neurodegenerative Spinocerebellar ataxias
Pathobiological
Pathogenesis
Pathogenic
Phenotype
Protein
Spinocerebellar Ataxias
Toxicity

Semantics

Type Source Name
gene UNIPROT LARGE1
disease MESH development
gene UNIPROT SLC6A4
disease MESH genetic disorders
disease MESH spinocerebellar ataxias
gene UNIPROT HTT

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