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ARE SYNUCLEINOPATHIES PRION DISEASES?
Patrik Brundin, MD, PhD Center for Neurodegenerative Science
Van Andel Research Institute Grand Rapids, Michigan, USA
Alzforum WebinarApril 8, 2016
Evidence from:
Post-mortem studies Cell culture experiments Animal models
Why should synucleinopathies be called prion diseases?
Lewy bodies can develop in healthy immature neurons grafted to PD (but not in HD) patients
Why should synucleinopathies be called prion diseases?
Phospho-S129-α-synuclein
Ubiquitin Thioflavin S
Li et al. 2008 and 2010.
Cell culture models demonstrate cell-to-cell transfer and seeding
α-synuclein Release uptake seeding transport
Vekrellis et al. 2011
Why should synucleinopathies be called prion diseases?
Injections can trigger progressive α-synucleinopathy that follows anatomically distinct neural pathways and induces functional deficits
• mouse brain extracts containing α-synuclein aggregates • recombinant α-synuclein fibrils • autopsy-derived brain extracts (PD, DLB, MSA) • peripheral inoculation is effective
Why should synucleinopathies be called prion diseases?
Injections can trigger progressive α-synucleinopathy that follows anatomically distinct neural pathways and induces functional deficits
• mouse brain extracts containing α-synuclein aggregates • recombinant α-synuclein fibrils • autopsy-derived brain extracts (PD, DLB, MSA) • peripheral inoculation is effective
PNAS 2013
Mouse brain
Recombinant fibrils
DLB
MSA
PD
Why should synucleinopathies be called prion diseases?
Injections can trigger progressive α-synucleinopathy that follows anatomically distinct neural pathways and induces functional deficits
• mouse brain extracts containing α-synuclein aggregates • recombinant α-synuclein fibrils • autopsy-derived brain extracts (PD, DLB, MSA) • peripheral inoculation is effective
Why should synucleinopathies be called prion diseases?
Injections can trigger progressive α-synucleinopathy that follows anatomically distinct neural pathways and induces functional deficits
• mouse brain extracts containing α-synuclein aggregates • recombinant α-synuclein fibrils • autopsy-derived brain extracts (PD, DLB, MSA) • peripheral inoculation is effective
Normal mice
α-synuclein fibrils into olfactory bulb
Spreading along anatomical pathways
Rey et al. submitted
Spreading of Pser129 α-syn pathology
Rey et al. submitted
Rey et al. submitted
1 mo after α-synuclein fibril injection
Thioflavin S staining (green) Nuclear stain (blue)
Thioflavin S-positive aggregates and behavioural deficits
Odor retention test
Delay
The fundamental molecular mechanism that unifies the templating capacity of prion-like proteins is the nucleated transformation of protein conformation.
In this spirit, we suggest that “prion” should be defined broadly as a “proteinaceous nucleating particle” (rather than a “proteinaceous infectious particle”).
Adapted from Walker and Jucker, Annu Rev Neurosci 2015
Expanding the prion concept
This expanded and refined definition could help to obviate unnecessary confusion and concern about the communicability of noninfectious proteopathies and speed acceptance of this important paradigm within the biomedical community.
….allows the prudent inclusion of noninfectious proteopathies under the umbrella of the prion concept.
Expanding the prion concept
Adapted from Walker and Jucker, Annu Rev Neurosci 2015
Concluding remarks - α-synuclein
• Release, uptake, seeding, transport
• Transfer between brain regions is gradual and anatomically faithful
• Peripheral inoculation is effective
• Emerging evidence for α-synuclein strains
• Propagated pathology causes functional deficits