PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins.
Alzheimer’s disease
Aβ
Dementia with Lewy bodies
Prion protein
Tau
α-Synuclein
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
19
11
2019
accepted:
10
12
2019
revised:
10
12
2019
pubmed:
20
12
2019
medline:
18
5
2021
entrez:
20
12
2019
Statut:
ppublish
Résumé
Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aβ aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aβ cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer's disease, dementia with Lewy bodies, and Pick's disease, we demonstrate that Aβ, α-synuclein and tau are toxic to neurons in a manner that requires PrP
Identifiants
pubmed: 31853635
doi: 10.1007/s00401-019-02114-9
pii: 10.1007/s00401-019-02114-9
pmc: PMC7035229
doi:
Substances chimiques
Amyloid beta-Peptides
0
Prions
0
alpha-Synuclein
0
tau Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
503-526Subventions
Organisme : Medical Research Council
ID : MC_U123160657
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : T32 AG000222
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG062421
Pays : United States
Organisme : Medical Research Council
ID : MC_UP_1604/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/8
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/9
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400713
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R21 AG053827
Pays : United States
Commentaires et corrections
Type : CommentIn
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