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
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 qu...
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doaj-6b5adfc66b214f258b9f18ae019b793d2020-11-25T03:01:30ZengBMCActa Neuropathologica Communications2051-59602020-08-018112310.1186/s40478-020-01026-0Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathyAllison J. Schaser0Teresa L. Stackhouse1Leah J. Weston2Patrick C. Kerstein3Valerie R. Osterberg4Claudia S. López5Dennis W. Dickson6Kelvin C. Luk7Charles K. Meshul8Randall L. Woltjer9Vivek K. Unni10Department of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science UniversityDepartment of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science UniversityDepartment of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science UniversityVollum Institute, Oregon Health and Science UniversityDepartment of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science UniversityMultiscale Microscopy Core, Oregon Health and Science UniversityDepartment of Neuroscience, Mayo ClinicDepartment of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of MedicineResearch Services, Veterans Affairs Medical CenterDepartment of Pathology, Oregon Health and Science UniversityDepartment of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science UniversityAbstract 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.http://link.springer.com/article/10.1186/s40478-020-01026-0SynucleinopathiesParkinson’s diseaseDementia with Lewy bodiesAlpha-synucleinLewy bodyTrans-synaptic spread |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Allison J. Schaser Teresa L. Stackhouse Leah J. Weston Patrick C. Kerstein Valerie R. Osterberg Claudia S. López Dennis W. Dickson Kelvin C. Luk Charles K. Meshul Randall L. Woltjer Vivek K. Unni |
spellingShingle |
Allison J. Schaser Teresa L. Stackhouse Leah J. Weston Patrick C. Kerstein Valerie R. Osterberg Claudia S. López Dennis W. Dickson Kelvin C. Luk Charles K. Meshul Randall L. Woltjer Vivek K. Unni 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 Acta Neuropathologica Communications Synucleinopathies Parkinson’s disease Dementia with Lewy bodies Alpha-synuclein Lewy body Trans-synaptic spread |
author_facet |
Allison J. Schaser Teresa L. Stackhouse Leah J. Weston Patrick C. Kerstein Valerie R. Osterberg Claudia S. López Dennis W. Dickson Kelvin C. Luk Charles K. Meshul Randall L. Woltjer Vivek K. Unni |
author_sort |
Allison J. Schaser |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2020-08-01 |
description |
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. |
topic |
Synucleinopathies Parkinson’s disease Dementia with Lewy bodies Alpha-synuclein Lewy body Trans-synaptic spread |
url |
http://link.springer.com/article/10.1186/s40478-020-01026-0 |
work_keys_str_mv |
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