Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD
(2020) In Proceedings of the National Academy of Sciences of the United States of America 117(26). p.15209-15220- Abstract
Preclinical assessment of the therapeutic potential of dopamine (DA) neuron replacement in Parkinson's disease (PD) has primarily been performed in the 6-hydroxydopamine toxin model. While this is a good model to assess graft function, it does not reflect the pathological features or progressive nature of the disease. In this study, we establish a humanized transplantation model of PD that better recapitulates the main disease features, obtained by coinjection of preformed human α-synuclein (α-syn) fibrils and adeno-associated virus (AAV) expressing human wild-type α-syn unilaterally into the rat substantia nigra (SN). This model gives rise to DA neuron dysfunction and progressive loss of DA neurons from the SN and terminals in the... (More)
Preclinical assessment of the therapeutic potential of dopamine (DA) neuron replacement in Parkinson's disease (PD) has primarily been performed in the 6-hydroxydopamine toxin model. While this is a good model to assess graft function, it does not reflect the pathological features or progressive nature of the disease. In this study, we establish a humanized transplantation model of PD that better recapitulates the main disease features, obtained by coinjection of preformed human α-synuclein (α-syn) fibrils and adeno-associated virus (AAV) expressing human wild-type α-syn unilaterally into the rat substantia nigra (SN). This model gives rise to DA neuron dysfunction and progressive loss of DA neurons from the SN and terminals in the striatum, accompanied by extensive α-syn pathology and a prominent inflammatory response, making it an interesting and relevant model in which to examine long-term function and integrity of transplanted neurons in a PD-like brain. We transplanted DA neurons derived from human embryonic stem cells (hESCs) into the striatum and assessed their survival, growth, and function over 6 to 18 wk. We show that the transplanted cells, even in the presence of ongoing pathology, are capable of innervating the DA-depleted striatum. However, on closer examination of the grafts, we found evidence of α-syn pathology in the form of inclusions of phosphorylated α-syn in a small fraction of the grafted DA neurons, indicating host-to-graft transfer of α-syn pathology, a phenomenon that has previously been observed in PD patients receiving fetal tissue grafts but has not been possible to demonstrate and study in toxin-based animal models.
(Less)
- author
- Hoban, Deirdre B LU ; Shrigley, Shelby LU ; Mattsson, Bengt LU ; Breger, Ludivine S LU ; Jarl, Ulla LU ; Cardoso, Tiago LU ; Nelander Wahlestedt, Jenny LU ; Luk, Kelvin C ; Björklund, Anders LU and Parmar, Malin LU
- organization
-
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Developmental and Regenerative Neurobiology (research group)
- Active and Healthy Ageing Research Group (research group)
- Molecular Neurogenetics (research group)
- Regeneration in Movement Disorders (research group)
- Neurology, Lund
- publishing date
- 2020-06-30
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 117
- issue
- 26
- pages
- 15209 - 15220
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:85087468680
- pmid:32541058
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.2001305117
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2020 the Author(s). Published by PNAS.
- id
- 55037b63-2db7-4ce1-9e7c-a5390af19d1c
- date added to LUP
- 2020-06-17 13:23:39
- date last changed
- 2024-09-20 00:00:21
@article{55037b63-2db7-4ce1-9e7c-a5390af19d1c, abstract = {{<p>Preclinical assessment of the therapeutic potential of dopamine (DA) neuron replacement in Parkinson's disease (PD) has primarily been performed in the 6-hydroxydopamine toxin model. While this is a good model to assess graft function, it does not reflect the pathological features or progressive nature of the disease. In this study, we establish a humanized transplantation model of PD that better recapitulates the main disease features, obtained by coinjection of preformed human α-synuclein (α-syn) fibrils and adeno-associated virus (AAV) expressing human wild-type α-syn unilaterally into the rat substantia nigra (SN). This model gives rise to DA neuron dysfunction and progressive loss of DA neurons from the SN and terminals in the striatum, accompanied by extensive α-syn pathology and a prominent inflammatory response, making it an interesting and relevant model in which to examine long-term function and integrity of transplanted neurons in a PD-like brain. We transplanted DA neurons derived from human embryonic stem cells (hESCs) into the striatum and assessed their survival, growth, and function over 6 to 18 wk. We show that the transplanted cells, even in the presence of ongoing pathology, are capable of innervating the DA-depleted striatum. However, on closer examination of the grafts, we found evidence of α-syn pathology in the form of inclusions of phosphorylated α-syn in a small fraction of the grafted DA neurons, indicating host-to-graft transfer of α-syn pathology, a phenomenon that has previously been observed in PD patients receiving fetal tissue grafts but has not been possible to demonstrate and study in toxin-based animal models.</p>}}, author = {{Hoban, Deirdre B and Shrigley, Shelby and Mattsson, Bengt and Breger, Ludivine S and Jarl, Ulla and Cardoso, Tiago and Nelander Wahlestedt, Jenny and Luk, Kelvin C and Björklund, Anders and Parmar, Malin}}, issn = {{1091-6490}}, language = {{eng}}, month = {{06}}, number = {{26}}, pages = {{15209--15220}}, publisher = {{National Academy of Sciences}}, series = {{Proceedings of the National Academy of Sciences of the United States of America}}, title = {{Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD}}, url = {{https://lup.lub.lu.se/search/files/100828213/Hoban_pdf_publication_in_pnas.pdf}}, doi = {{10.1073/pnas.2001305117}}, volume = {{117}}, year = {{2020}}, }