Journal
CELL SYSTEMS
Volume 13, Issue 4, Pages 304-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2022.01.005
Keywords
-
Categories
Funding
- CHDI Foundation, USA
- NIH [NS077926, NS090914]
- AG/NIA/NIH [R01 AG057339]
- Helmholtz Association (iMed, Germany)
- Helmholtz Association (Helmholtz-Israel Initiative on Personalized Medicine, Germany)
Ask authors/readers for more resources
Huntington disease is a neurodegenerative disorder with multifactorial pathobiology. This study identifies perturbed protein-protein interactions involving the huntingtin protein, suggesting the influence of cellular factors on disease progression. The findings reveal that these interactions are affected by expanded polyglutamine and are associated with impaired synaptic communication and lysosomal acidification.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available