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Updated: May 4, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
A large scale Huntingtin protein interaction network implicates Rho GTPase signaling pathways in Huntington disease
Cendrine Tourette1, Biao Li1, Russell Bell2
1Buck Institute for Research on Aging, Novato, California 94945.
Insights
Huntington disease (HD) involves CAG expansion in the HTT gene. Researchers found that huntingtin-interacting proteins (HIPs) are linked to pathways affected in HD, suggesting new therapeutic targets for this neurodegenerative disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington disease (HD) is an inherited neurodegenerative disorder.
- It is caused by a CAG expansion mutation in the huntingtin (HTT) gene.
- The precise molecular mechanisms underlying HD pathogenesis remain incompletely understood.
Purpose of the Study:
- To identify and characterize proteins that interact with huntingtin (HTT).
- To investigate the functional roles of these HTT-interacting proteins (HIPs) in HD pathology.
- To explore the involvement of HTT in cellular processes like membrane dynamics.
Main Methods:
- Yeast two-hybrid screening to identify protein-protein interactions.
- Bioinformatic analysis of functional annotations for identified protein networks.
- Validation of HIPs' roles in mutant HTT toxicity using cellular models.
- Confocal microscopy to assess co-localization and cellular dynamics.
Main Results:
- A large network of 3235 interactions among 2141 interconnected proteins (HIPs) was identified.
- HIPs are significantly enriched in pathways relevant to HD, including mTOR, Rho GTPase signaling, and oxidative stress.
- Specific Rho GTPase signaling components (BAIAP2, EZR, PIK3R1, PAK2, RAC1) were validated as modifiers of mutant HTT toxicity.
- Huntingtin (Htt) was found to co-localize with BAIAP2 in filopodia, and mutant HTT disrupts filopodial dynamics.
Conclusions:
- Huntingtin protein (HTT) plays a direct role in membrane dynamics, cell attachment, and motility.
- Dysregulation of Rho GTPase signaling and related pathways contributes to Huntington disease pathogenesis.
- Identified HIPs and pathways represent potential therapeutic targets for HD.
Abstract:
Huntington disease (HD) is an inherited neurodegenerative disease caused by a CAG expansion in the HTT gene. Using yeast two-hybrid methods, we identified a large set of proteins that interact with huntingtin (HTT)-interacting proteins. This network, composed of HTT-interacting proteins (HIPs) and proteins interacting with these primary nodes, contains 3235 interactions among 2141 highly interconnected proteins. Analysis of functional annotations of these proteins indicates that primary and secondary HIPs are enriched in pathways implicated in HD, including mammalian target of rapamycin, Rho GTPase signaling, and oxidative stress response. To validate roles for HIPs in mutant HTT toxicity, we show that the Rho GTPase signaling components, BAIAP2, EZR, PIK3R1, PAK2, and RAC1, are modifiers of mutant HTT toxicity. We also demonstrate that Htt co-localizes with BAIAP2 in filopodia and that mutant HTT interferes with filopodial dynamics. These data indicate that HTT is involved directly in membrane dynamics, cell attachment, and motility. Furthermore, they implicate dysregulation in these pathways as pathological mechanisms in HD.
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