Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease.
AMPA receptors
Arp2/3
D. melanogaster
LuTHy
SNARE
immunoaffinity purification-mass spectrometry
label-free quantification
metabolic labeling
protein interactions
synaptic biology
vesicular trafficking
Journal
Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080
Informations de publication
Date de publication:
20 04 2022
20 04 2022
Historique:
received:
15
06
2021
revised:
18
11
2021
accepted:
24
01
2022
pubmed:
13
2
2022
medline:
26
4
2022
entrez:
12
2
2022
Statut:
ppublish
Résumé
Huntington disease (HD) is a monogenic neurodegenerative disorder with one causative gene, huntingtin (HTT). Yet, HD pathobiology is multifactorial, suggesting that cellular factors influence disease progression. Here, we define HTT protein-protein interactions (PPIs) perturbed by the mutant protein with expanded polyglutamine in the mouse striatum, a brain region with selective HD vulnerability. Using metabolically labeled tissues and immunoaffinity purification-mass spectrometry, we establish that polyglutamine-dependent modulation of HTT PPI abundances and relative stability starts at an early stage of pathogenesis in a Q140 HD mouse model. We identify direct and indirect PPIs that are also genetic disease modifiers using in-cell two-hybrid and behavioral assays in HD human cell and Drosophila models, respectively. Validated, disease-relevant mHTT-dependent interactions encompass mediators of synaptic neurotransmission (SNAREs and glutamate receptors) and lysosomal acidification (V-ATPase). Our study provides a resource for understanding mHTT-dependent dysfunction in cortico-striatal cellular networks, partly through impaired synaptic communication and endosomal-lysosomal system. A record of this paper's Transparent Peer Review process is included in the supplemental information.
Identifiants
pubmed: 35148841
pii: S2405-4712(22)00040-0
doi: 10.1016/j.cels.2022.01.005
pmc: PMC9317655
mid: NIHMS1780257
pii:
doi:
Substances chimiques
Huntingtin Protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
304-320.e5Subventions
Organisme : NIA NIH HHS
ID : R01 AG057339
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS077926
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS090914
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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