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