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Acta Neuropathol. 2019 Dec 18. doi: 10.1007/s00401-019-02114-9. [Epub ahead of print]

PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins.

Author information

1
Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Hale Building for Transformative Medicine, 60 Fenwood Road, Boston, MA, 02115, USA.
2
Centre for Discovery Brain Sciences and UK Dementia Research Institute, University of Edinburgh, Edinburgh, EH89JZ, UK.
3
Program for Interdisciplinary Neuroscience, Brigham and Women's Hospital, Boston, MA, 02115, USA.
4
Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA.
5
MRC Prion Unit at UCL, UCL Institute of Prion Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
6
Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA.
7
Neuroscience, IMED Biotechnology Unit, AstraZeneca, Cambridge, CB21 6GH, UK.
8
Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Hale Building for Transformative Medicine, 60 Fenwood Road, Boston, MA, 02115, USA. dwalsh3@bwh.harvard.edu.

Abstract

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 PrPC. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.

KEYWORDS:

Alzheimer’s disease; Aβ; Dementia with Lewy bodies; Prion protein; Tau; α-Synuclein

PMID:
31853635
DOI:
10.1007/s00401-019-02114-9

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