scholarly journals Taming the Huntington’s Disease Proteome: What Have We Learned?

2021 ◽  
pp. 1-19
Author(s):  
Connor Seeley ◽  
Kimberly B. Kegel-Gleason
Keyword(s):  
Biological Sciences ◽  
Mass Spectrometry ◽  
Systems Biology ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Interacting Proteins ◽  
Computational Approaches ◽  
Physical Technique ◽  
Precise Analysis ◽  
Disease Pathways

Mass spectrometry (MS) is a physical technique used to identify specific chemicals and molecules by precise analysis of their mass and charge; this technology has been adapted for biological sciences applications. Investigators have used MS to identify differential expressions of proteins in Huntington’s disease (HD), to discover Huntingtin (HTT) interacting proteins and to analyze HTT proteoforms. Using systems biology and computational approaches, data from MS screens have been leveraged to find differentially expressed pathways. This review summarizes the data from most of the MS studies done in the HD field in the last 20 years and compares it to the protein data reported before the use of MS technology. The MS results validate early findings in the field such as differential expression of PDE10a and DARPP-32 and identify new changes. We offer a perspective on the MS approach in HD, particularly for identification of disease pathways, the challenges in interpreting data across different studies, and its application to protein studies moving forward.

scholarly journals Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

2021 ◽  
pp. 1-13
Author(s):  
Karen A. Sap ◽  
Arzu Tugce Guler ◽  
Aleksandra Bury ◽  
Dick Dekkers ◽  
Jeroen A.A. Demmers ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Cortex ◽  
Full Length ◽  
Biological Processes ◽  
Interacting Proteins ◽  
Mutant Huntingtin ◽  
Wild Type ◽  
Mutant Huntingtin Protein ◽  
Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

Novel Metabolite Biomarkers of Huntington’s Disease As Detected by High-Resolution Mass Spectrometry

2016 ◽  
Vol 15 (5) ◽  
pp. 1592-1601 ◽  
Author(s):  
Stewart F. Graham ◽  
Praveen Kumar ◽  
Ray O. Bahado-Singh ◽  
Andrew Robinson ◽  
David Mann ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Resolution Mass Spectrometry ◽  
High Resolution Mass ◽  
Resolution Mass

Transcriptional profiles for distinct aggregation states of mutant Huntingtin exon 1 protein unmask new Huntington's disease pathways

2017 ◽  
Vol 83 ◽  
pp. 103-112 ◽  
Author(s):  
Nagaraj S. Moily ◽  
Angelique R. Ormsby ◽  
Aleksandar Stojilovic ◽  
Yasmin M. Ramdzan ◽  
Jeannine Diesch ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Transcriptional Profiles ◽  
Exon 1 ◽  
Disease Pathways

scholarly journals HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1

2021 ◽  
Author(s):  
Rachel J. Harding ◽  
Justin C. Deme ◽  
Johannes F. Hevler ◽  
Sem Tamara ◽  
Alexander Lemak ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Domain Architecture ◽  
Native Mass Spectrometry ◽  
Polyglutamine Expansion ◽  
X Ray Scattering ◽  
Exon 1 ◽  
Functional Relevance

AbstractHuntington’s disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. We demonstrate in vivo that HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass-spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The polyglutamine tract containing N-terminal exon 1 region of HTT is dynamic, but shows greater conformational variety in the mutant than wildtype exon 1. By providing novel insight into the structural consequences of HTT polyglutamine expansion, our data provide a foundation for future functional and drug discovery studies targeting Huntington’s disease.

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