Prion-like propagation of alpha-synuclein aggregates in the brain of wild-type mice

Transcription

1 Prion-like propagation of alpha-synuclein aggregates in the brain of wild-type mice Nolwen L. Rey, PhD Patrik Brundin s Laboratory, Van Andel Research Institute Grand Rapids, Michigan, USA 15th Annual Mild Cognitive Impairment (MCI) Symposium 14 january 2017 No conflict of interest to disclose

2 - Synuclein and Parkinson s disease Mandel et al Lewy bodies (LB) and Lewy neurites, hallmarks of Parkinson s disease -Synuclein Misfolded and hyper phosphorylated α-syn Death of midbrain dopamine neurons is key to motor symptoms Braak et al Cell and Tissue Research Dauer and Prezedborski, 2003, Neuron Non-motor symptoms are also a major issue

3 Fetal neuron transplants in Parkinson s disease Lund Fetal DA neurons Grafting Multiple donors for each brain

4 Young transplanted neurons with Lewy bodies TH in Substantia Nigra: α-synuclein in Striatal graft: in Striatal graft: Lewy bodies in grafted neurons in at least 9 cases from 5 different surgical centers Li et al. 2008, Nat Med, 2010, Mov Dis

5 Cell-to-cell transfer: Prion-like propagation hypothesis Donor cell Recipient cell 1- Release 2- Uptake 3- Seeding Adapted from Angot et al. 2010

6 First animal model of cell-to-cell transfer Graft Fetal mesencephalic tissue AAV hu α-syn Angot et al PloS One Modified from Kirik et al. 2004, Nat Neurosc

7 -Synuclein seeding in vivo, and propagation Brain lysate Synthetic PFFs Mougenot et al Neurobiology of Aging Adapted from Polymenidou and Cleveland, 2012 JEM Luk et al J Exp Med Propagation along connections (as suggested in humans)?

8 Parkinson s disease staging Hawkes et al , 2009, 2010 Braak et al. 2002, 2003, 2004 Neocortex (secondary & primary) Neocortex association Mesocortex Substantia nigra, Amygdala Locus coeruleus Dorsal IX / X nucleus, Olfactory bulb Hyposmia Constipation Bladder disorder Sleep disorder Depression Presymptomatic Phase Unilateral tremor Rigidity Akinesia Poor balance Time (years) Symptomatic Phase Falls Cognitive decline Dementia Dependency Stage 2 routes of progression?

9 Olfactory system in Parkinson s disease α-syn pathology: first in the olfactory bulb (then in the DMX) (Beach et al. 2009, Braak and Del Tredici 2016) Olfactory dysfunction: > 4 years before clinical diagnosis of PD Beach et al. 2009, Acta Neuropathologica Prevalence: 75-96% in patients with PD (Attems et al Acta Neuropathologica) The olfactory system is involved in prodromal Parkinson s disease

10 Olfactory bulb pathology model Cell-to-cell transfer and propagation of α-syn during prodromal PD are potential therapeutic targets Create a model of progressive α-syn pathology of direct relevance to prodromal PD Rey et al, JEM 2016

11 Olfactory bulb pathology model α-syn fibrils (PFFs) 250um [α-syn monomer and PBS as controls] Injection into the olfactory bulb Wild type mice 1 month 3 months 6 months 12 months Olfactory tests α-syn neuropathology Rey et al, JEM 2016

12 Pser129 -syn pathology in olfactory structures Rey et al, JEM 2016

13 Pser129 pathology -syn propagation Rey et al, JEM 2016

14 Inclusions positive for markers of Lewy bodies in neurons Rey et al, JEM 2016

15 Odorant dilution Progressive olfactory deficits Rey et al, JEM 2016 Odorant detection threshold >10-2 >10-2 >10-2 Controls PBS mms mpffs Severe deficit of odor detection in PFFs-injected mice mo 3mo 6mo 12mo Time after injection Severe deficit of odor retention in PFFs-injected mice

16 Concluding remarks Neuron-to-neuron transfer in vivo Seeding in vivo Propagation of pathology between distal brain regions, following neuronal connections Mechanisms of initiation of pathology? Mechanisms of transmission between cells/ distal brain regions? Non-neuronal cells involved in propagation?

17 Brundin Lab- Grand Rapids Patrik Brundin Sonia George Emily Schulz Jennifer Steiner Darcy Marckini Former Brundin Lab- Lund, Sweden Elodie Angot Alicja Flasch Ulrika Nordström Marie Persson-Vejgården Acknowledgements V Lee s lab, UPenn Philadelphia Kelvin C Luk Virginia M-Y Lee John Trojanowski R Melki s lab, CNRS France Ronald Melki Luc Bousset J Ma s Lab -VAI Jiyan Ma Xinhe Wang Katelyn Becker Vivarium VAI Elissa Boguslawski Stephen Bowman Bryn Eagleson Tristan Kempston Statistical core VAI Zach Madaj Mary Winn Research Funding Van Andel Research Institute Peter C. & Emajean Cook Foundation Multipark (Lund) ERC (Lund) Contact me at: Nolwen.Rey@vai.org