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Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies
Synucleinopathies are a group of neurodegenerative disorders sharing the common feature of misfolding and accumulation of the presynaptic protein α‐synuclein (α‐syn) into insoluble aggregates. Within this diverse group, Dementia with Lewy Bodies (DLB) is characterized by the aberrant accumulation of...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464354/ https://www.ncbi.nlm.nih.gov/pubmed/28225193 http://dx.doi.org/10.1002/sctm.16-0362 |
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author | Goldberg, Natalie R.S. Marsh, Samuel E. Ochaba, Joseph Shelley, Brandon C. Davtyan, Hayk Thompson, Leslie M. Steffan, Joan S. Svendsen, Clive N. Blurton‐Jones, Mathew |
author_facet | Goldberg, Natalie R.S. Marsh, Samuel E. Ochaba, Joseph Shelley, Brandon C. Davtyan, Hayk Thompson, Leslie M. Steffan, Joan S. Svendsen, Clive N. Blurton‐Jones, Mathew |
author_sort | Goldberg, Natalie R.S. |
collection | PubMed |
description | Synucleinopathies are a group of neurodegenerative disorders sharing the common feature of misfolding and accumulation of the presynaptic protein α‐synuclein (α‐syn) into insoluble aggregates. Within this diverse group, Dementia with Lewy Bodies (DLB) is characterized by the aberrant accumulation of α‐syn in cortical, hippocampal, and brainstem neurons, resulting in multiple cellular stressors that particularly impair dopamine and glutamate neurotransmission and related motor and cognitive function. Recent studies show that murine neural stem cell (NSC) transplantation can improve cognitive or motor function in transgenic models of Alzheimer's and Huntington's disease, and DLB. However, examination of clinically relevant human NSCs in these models is hindered by the challenges of xenotransplantation and the confounding effects of immunosuppressant drugs on pathology and behavior. To address this challenge, we developed an immune‐deficient transgenic model of DLB that lacks T‐, B‐, and NK‐cells, yet exhibits progressive accumulation of human α‐syn (h‐α‐syn)‐laden inclusions and cognitive and motor impairments. We demonstrate that clinically relevant human neural progenitor cells (line CNS10‐hNPCs) survive, migrate extensively and begin to differentiate preferentially into astrocytes following striatal transplantation into this DLB model. Critically, grafted CNS10‐hNPCs rescue both cognitive and motor deficits after 1 and 3 months and, furthermore, restore striatal dopamine and glutamate systems. These behavioral and neurochemical benefits are likely achieved by reducing α‐syn oligomers. Collectively, these results using a new model of DLB demonstrate that hNPC transplantation can impact a broad array of disease mechanisms and phenotypes and suggest a cellular therapeutic strategy that should be pursued. Stem Cells Translational Medicine 2017;6:1477–1490 |
format | Online Article Text |
id | pubmed-5464354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54643542017-11-24 Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies Goldberg, Natalie R.S. Marsh, Samuel E. Ochaba, Joseph Shelley, Brandon C. Davtyan, Hayk Thompson, Leslie M. Steffan, Joan S. Svendsen, Clive N. Blurton‐Jones, Mathew Stem Cells Transl Med Translational Research Articles and Reviews Synucleinopathies are a group of neurodegenerative disorders sharing the common feature of misfolding and accumulation of the presynaptic protein α‐synuclein (α‐syn) into insoluble aggregates. Within this diverse group, Dementia with Lewy Bodies (DLB) is characterized by the aberrant accumulation of α‐syn in cortical, hippocampal, and brainstem neurons, resulting in multiple cellular stressors that particularly impair dopamine and glutamate neurotransmission and related motor and cognitive function. Recent studies show that murine neural stem cell (NSC) transplantation can improve cognitive or motor function in transgenic models of Alzheimer's and Huntington's disease, and DLB. However, examination of clinically relevant human NSCs in these models is hindered by the challenges of xenotransplantation and the confounding effects of immunosuppressant drugs on pathology and behavior. To address this challenge, we developed an immune‐deficient transgenic model of DLB that lacks T‐, B‐, and NK‐cells, yet exhibits progressive accumulation of human α‐syn (h‐α‐syn)‐laden inclusions and cognitive and motor impairments. We demonstrate that clinically relevant human neural progenitor cells (line CNS10‐hNPCs) survive, migrate extensively and begin to differentiate preferentially into astrocytes following striatal transplantation into this DLB model. Critically, grafted CNS10‐hNPCs rescue both cognitive and motor deficits after 1 and 3 months and, furthermore, restore striatal dopamine and glutamate systems. These behavioral and neurochemical benefits are likely achieved by reducing α‐syn oligomers. Collectively, these results using a new model of DLB demonstrate that hNPC transplantation can impact a broad array of disease mechanisms and phenotypes and suggest a cellular therapeutic strategy that should be pursued. Stem Cells Translational Medicine 2017;6:1477–1490 John Wiley and Sons Inc. 2017-02-22 /pmc/articles/PMC5464354/ /pubmed/28225193 http://dx.doi.org/10.1002/sctm.16-0362 Text en © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Translational Research Articles and Reviews Goldberg, Natalie R.S. Marsh, Samuel E. Ochaba, Joseph Shelley, Brandon C. Davtyan, Hayk Thompson, Leslie M. Steffan, Joan S. Svendsen, Clive N. Blurton‐Jones, Mathew Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies |
title | Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies |
title_full | Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies |
title_fullStr | Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies |
title_full_unstemmed | Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies |
title_short | Human Neural Progenitor Transplantation Rescues Behavior and Reduces α‐Synuclein in a Transgenic Model of Dementia with Lewy Bodies |
title_sort | human neural progenitor transplantation rescues behavior and reduces α‐synuclein in a transgenic model of dementia with lewy bodies |
topic | Translational Research Articles and Reviews |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464354/ https://www.ncbi.nlm.nih.gov/pubmed/28225193 http://dx.doi.org/10.1002/sctm.16-0362 |
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