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Identification of full length wild-type and mutant huntingtin interacting proteins by crosslinking immunoprecipitation in mice brain cortex

ABSTRACT: Huntington’s Disease is a neurodegenerative disorder caused by a CAG expansion in exon1 of the huntingtin (Htt) gene. The resulting polyglutamine expansion in the ubiquitously expressed mutant Htt (mHtt) protein leads to selective neurodegeneration. In this study we set out to identify interacting proteins of full length wild-type and mHtt protein in the mice cortex brain region in order to get a better understanding of the processes involved in HD pathology.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Huntington Disease

SUBMITTER: Arzu Tugce Guler

LAB HEAD: Eric Reits

PROVIDER: PXD024254 | Pride | 2021-06-21

REPOSITORIES: Pride

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			Action	DRS
	130619_musmusculus_reviewed_17010.fasta	Fasta
	2079_F_KarenSap_01.raw	Raw
	2079_F_KarenSap_02.raw	Raw
	2079_F_KarenSap_03.raw	Raw
	2079_F_KarenSap_04.raw	Raw

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Publications

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

Sap Karen A KA Guler Arzu Tugce AT Bury Aleksandra A Dekkers Dick D Demmers Jeroen A A JAA Reits Eric A EA

Journal of Huntington's disease 20210101 3

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>Full-length huntingtin with 2 ...[more]

PMID: 34151850

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Huntingtin polyglutamine expansion modulates protein interaction dynamics in the striatum

Project description:Huntington’s disease is a monogenic disorder, with only one known causative gene, huntingtin (HTT). Expansion of a trinucleotide (CAG) repeat within the HTT gene results in a mutant protein containing polyglutamine (polyQ) stretches. While mutant HTT is the primary driver of cellular degeneration in the brain, the molecular and cellular mechanisms are incompletely understood. To further understand the role of polyQ in disease pathogenesis, we studied the dynamics of HTT protein-protein interactions (PPIs) in the striatum of mice with wild-type (Q20) and mutant (Q140) HTT at pre-symptomatic and manifest HD ages using label-free and isotope-labeled IP-MS approaches. Combining these approaches, we demonstrated that HTT PPI dynamics are distinct in early and later disease phases. Computational analysis pointed to early protein interaction changes involving synaptic transmission and vesicle fusion functions, while later interactions underlie changes in synapse morphogenesis and impact the actin cytoskeletal network.

2022-02-20 | PXD025510 | Pride

PTMs of HTT protein - Post-translational modifications (PTMs), identified on endogenous huntingtin, cluster within proteolytic domains between HEAT repeats

Project description:Post-translational modifications (PTMs) of proteins regulate various cellular processes. PTMs of polyglutamine-expanded huntingtin (Htt) protein, causative of Huntington’s disease (HD), are likely modulators of HD pathogenesis. Previous studies have identified and characterized several PTMs on exogenously expressed Htt fragments, however none of these studies were designed to systematically characterize PTMs on the endogenous full-length Htt protein.We found that full-length endogenous Htt, immunoprecipitated from HD knock-in mouse and human post mortem brain, is suitable for detection of PTMs by mass spectrometry. Using label-free mass spectrometry, we identified around 40 PTMs, of which half are novel. These findings will be instrumental in the further assembling the Htt PTM framework, and validate PTMs of Htt as promising therapeutic targets for HD.

2017-06-29 | PXD005753 | Pride

Site-Specific Ubiquitination of Pathogenic Huntingtin Attenuates its Deleterious Effects- PART2

Project description:Huntington’s disease (HD) is a progressive incurable neurodegenerative disorder characterized by motor and neuropsychiatric symptoms. It is caused by expansion of a CAG triplet in the N-terminal domain of exon 1 in the huntingtin (HTT) gene that codes for an expanded polyglutamine (polyQ) stretch in the protein product which becomes aggregation-prone. The mutant Htt (mHtt) aggregates are associated with components of the Ubiquitin-Proteasome System (UPS), suggesting that mHtt is marked for proteasomal degradation and that for reasons still debated are not properly degraded. We used a novel HD rat model, proteomic analysis, and long-term live neuronal imaging to characterize the effects of ubiquitination on aggregation of mHtt and its subsequent cellular response. We identified two lysine residues - 6 and 9 - in the first exon of mHtt that are specifically ubiquitinated in striatal and cortical brain tissues of mHtt-transgenic animals. Expression of mHtt exon 1 lacking these ubiquitination sites in cortical neurons and cultured cells was found to slow aggregate appearance rates and reduce their size, but at the same time increase the number of much smaller and less visible ones. Importantly, expression of this form of mHtt was associated with elevated death rates. Furthermore, proteomic analysis indicated that compared to cells expressing the protein that can be modified by ubiquitin, cells expressing the lysine-less protein did not activate protein synthetic pathways that enable the cell to cope with stress. Taken together, the findings suggest a novel role for ubiquitination - attenuation of the pathogenic effect of mHtt.

2020-06-30 | PXD019552 | Pride

Site-Specific Ubiquitination of Pathogenic Huntingtin Attenuates its Deleterious Effects

2020-06-30 | PXD019553 | Pride

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

Project description:Huntington’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 and in cell models 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 exon 1 region of HTT is dynamic but shows greater conformational variety in the polyglutamine expanded mutant than wildtype exon 1. Our data provide a foundation for future functional and drug discovery studies targeting Huntington’s disease and illuminate the structural consequences of HTT polyglutamine expansion.

2022-02-21 | PXD028313 | Pride

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

2022-09-09 | PXD028415 | Pride

Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease

Project description:Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type and mHTT are regulated by a stress-responsive upstream open reading frame, and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

2024-03-13 | PXD026012 | Pride

G3BP1-dependent suppression of polyglutamine aggregation in Huntington’s models and its failure upon stress granule formation

Project description:To define the interactome of huntingtin protein (HTT) in human neurons, we assessed interactors of HTT with coimmunoprecipitation experiments with huntingtin antibody or polyqlutamine antibody (it only recognizes mutant huntingtin protein with abnormal polyqlutamine expansion) in striatal neurons differentiated from control and patient-derived iPSC lines (HD-iPSCs). GFP antibody used as a negative control.

2022-12-02 | PXD037618 | Pride

Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [NGN2]

Project description:Expansion of the glutamine tract (poly-Q) in the protein Huntingtin (HTT) causes the neurodegenerative disorder Huntington’s disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered induced pluripotent stem cells to introduce a 70Q expansion or remove the poly-Q tract of HTT. 70Q introduction caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), which is involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics and elevated resting energy expenditure. Elimination of the poly-Q tract of HTT normalized CHCHD2 expression and mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early intervention target for HD.

2024-07-23 | GSE233914 | GEO

Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure [organoids]

2024-07-23 | GSE233895 | GEO