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

Erich E Wanker,Anne Ast,Franziska Schindler,Philipp Trepte,Sigrid Schnoegl

doi:10.1111/jnc.14853

Erich E Wanker, Anne Ast + Show 3 more

Open Access

https://doi.org/10.1111/jnc.14853

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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".

Highlights

Mutations are at the root of many human diseases
The detection and functional characterization of protein–protein interactions (PPIs) is of critical importance to gain a better understanding of cellular processes and disease phenotypes
Besides full-length mutant HTT (mHTT) with a pathogenic polyQ tract and a largely a-helical conformation (Guo et al 2018), a variety of other conformationally distinct mHTT protein species have been reported to be present in Huntington’s disease (HD) patient brains and disease models (Scherzinger et al 1997; DiFiglia et al 1997; Sathasivam et al 2010)

Summary

Various putatively pathogenic mHTT protein species have been described

Besides full-length mHTT with a pathogenic polyQ tract and a largely a-helical conformation (Guo et al 2018), a variety of other conformationally distinct mHTT protein species have been reported to be present in HD patient brains and disease models (Scherzinger et al 1997; DiFiglia et al 1997; Sathasivam et al 2010). Axonal transport Previous studies have shown that a protein complex consisting of full-length HTT and its interaction partner huntingtin-associated protein 1 (HAP1) regulates the transport of organelles and various types of membrane vesicles along axons (Fig. 3), in both anterograde and retrograde directions (Gauthier et al 2004; Wong and Holzbaur 2014). HAP1 interacts more strongly with mutant than wtHTT in yeast two-hybrid assays (Li et al 1995), suggesting that the expanded polyQ in full-length mHTT may abnormally stabilize this interaction in neurons This enhanced binding may in turn perturb the functionally important interaction between HAP1 and KIF5 motors, leading to a decrease in GABAA-receptor trafficking in neurons. The potential relevance of a loss of HIP14 function in HD is supported by genetic knock-out studies in mice, indicating that mice deficient in HIP14 and HIP14L (a HIP14 related protein) both recapitulate important features of HD (Singaraja et al 2011; Sutton et al 2013)

Mitochondrial fission and mitophagy

Future perspectives

Acknowledgments and conflict of interest disclosure