Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T a
- PDF / 3,933,420 Bytes
- 23 Pages / 595.276 x 790.866 pts Page_size
- 18 Downloads / 151 Views
Open Access
RESEARCH
Trans‑synaptic and retrograde axonal spread of Lewy pathology following pre‑formed fibril injection in an in vivo A53T alpha‑synuclein mouse model of synucleinopathy Allison J. Schaser1, Teresa L. Stackhouse1, Leah J. Weston1, Patrick C. Kerstein2, Valerie R. Osterberg1, Claudia S. López3, Dennis W. Dickson4, Kelvin C. Luk5, Charles K. Meshul6,7, Randall L. Woltjer8 and Vivek K. Unni1,9*
Abstract It is necessary to develop an understanding of the specific mechanisms involved in alpha-synuclein aggregation and propagation to develop disease modifying therapies for age-related synucleinopathies, including Parkinson’s disease and Dementia with Lewy Bodies. To adequately address this question, we developed a new transgenic mouse model of synucleinopathy that expresses human A53T SynGFP under control of the mouse prion protein promoter. Our characterization of this mouse line demonstrates that it exhibits several distinct advantages over other, currently available, mouse models. This new model allows rigorous study of the initial location of Lewy pathology formation and propagation in the living brain, and strongly suggests that aggregation begins in axonal structures with retrograde propagation to the cell body. This model also shows expeditious development of alpha-synuclein pathology following induction with small, in vitro-generated alpha-synuclein pre-formed fibrils (PFFs), as well as accelerated cell death of inclusion-bearing cells. Using this model, we found that aggregated alpha-synuclein somatic inclusions developed first in neurons, but later showed a second wave of inclusion formation in astrocytes. Interestingly, astrocytes appear to survive much longer after inclusion formation than their neuronal counterparts. This model also allowed careful study of peripheral-to-central spread of Lewy pathology after PFF injection into the hind limb musculature. Our results clearly show evidence of progressive, retrograde trans-synaptic spread of Lewy pathology through known neuroanatomically connected pathways in the motor system. As such, we have developed a promising tool to understand the biology of neurodegeneration associated with alpha-synuclein aggregation and to discover new treatments capable of altering the neurodegenerative disease course of synucleinopathies. Keywords: Synucleinopathies, Parkinson’s disease, Dementia with Lewy bodies, Alpha-synuclein, Lewy body, Transsynaptic spread, Neurodegeneration
*Correspondence: [email protected] 1 Department of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR 97239, USA Full list of author information is available at the end of the article
Introduction Age-related synucleinopathies including Parkinson disease (PD), Dementia with Lewy bodies (DLB), and Multiple Systems Atrophy (MSA) are common and debilitating neurodegenerative disorders that include both motor
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, whic
Data Loading...
