Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted.
Nat Commun
; 12(1): 4272, 2021 07 13.
Article
in En
| MEDLINE
| ID: mdl-34257293
ABSTRACT
The first exon of the huntingtin protein (HTTex1) important in Huntington's disease (HD) can form cross-ß fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-ß fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Huntington Disease
/
Neurodegenerative Diseases
/
Huntingtin Protein
Limits:
Humans
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2021
Document type:
Article
Affiliation country:
Estados Unidos