Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques
Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson's disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD-even when considering idiopathic forms of PD-h...
| Autores: | , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/114741 |
| Acceso en línea: | https://hdl.handle.net/10171/114741 |
| Access Level: | acceso abierto |
| Palabra clave: | GBA1 Parkinson’s disease Adeno-associated viral vectors Neuroprotection Synucleinopathies |
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Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaquesSucunza, D. (Diego)|||/items/c40063b2-c2e8-466b-aaa2-5a3acb7fb1f6Rico, A.J. (Alberto J.)|||/items/7a177958-067e-4900-943e-0271d63a5021Roda, E. (Elvira)|||/items/7ea91585-d2d9-4d11-aabf-4daab728ca1cCollantes, M. (María)|||/items/102ad3e7-3f57-4958-8e97-39af1c92626bGonzález-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191acRodriguez-Perez, A.I. (Ana I.)|||/items/4167ee59-145c-4ff4-a5ca-0482da3930fcPeñuelas-Sanchez, I. (Ivan)|||/items/7022e2fa-b3b0-48ed-8d39-2020cfae85a4Vazquez, A. (Alfonso)|||/items/7d5cb87e-5c97-4865-aea8-a4694ef0139fLabandeira-Garcia, J.L. (José L.)|||/items/6ff85c09-f91d-4c80-bb94-2763191534ebBroccoli, V. (Vania)|||/items/5c457f7e-0f40-47a7-996e-a243054aca6cLanciego-Pérez, J.L. (José Luis)|||/items/d2d4dbfe-4daf-4103-89ec-2ebf41b65cd1GBA1Parkinson’s diseaseAdeno-associated viral vectorsNeuroprotectionSynucleinopathiesMutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson's disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD-even when considering idiopathic forms of PD-has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders.MDPIDadun. Depósito Académico Digital Universidad de Navarra20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/114741reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1147412026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques |
| title |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques |
| spellingShingle |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques Sucunza, D. (Diego)|||/items/c40063b2-c2e8-466b-aaa2-5a3acb7fb1f6 GBA1 Parkinson’s disease Adeno-associated viral vectors Neuroprotection Synucleinopathies |
| title_short |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques |
| title_full |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques |
| title_fullStr |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques |
| title_full_unstemmed |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques |
| title_sort |
Glucocerebrosidase gene therapy induces alpha-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques |
| dc.creator.none.fl_str_mv |
Sucunza, D. (Diego)|||/items/c40063b2-c2e8-466b-aaa2-5a3acb7fb1f6 Rico, A.J. (Alberto J.)|||/items/7a177958-067e-4900-943e-0271d63a5021 Roda, E. (Elvira)|||/items/7ea91585-d2d9-4d11-aabf-4daab728ca1c Collantes, M. (María)|||/items/102ad3e7-3f57-4958-8e97-39af1c92626b González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac Rodriguez-Perez, A.I. (Ana I.)|||/items/4167ee59-145c-4ff4-a5ca-0482da3930fc Peñuelas-Sanchez, I. (Ivan)|||/items/7022e2fa-b3b0-48ed-8d39-2020cfae85a4 Vazquez, A. (Alfonso)|||/items/7d5cb87e-5c97-4865-aea8-a4694ef0139f Labandeira-Garcia, J.L. (José L.)|||/items/6ff85c09-f91d-4c80-bb94-2763191534eb Broccoli, V. (Vania)|||/items/5c457f7e-0f40-47a7-996e-a243054aca6c Lanciego-Pérez, J.L. (José Luis)|||/items/d2d4dbfe-4daf-4103-89ec-2ebf41b65cd1 |
| author |
Sucunza, D. (Diego)|||/items/c40063b2-c2e8-466b-aaa2-5a3acb7fb1f6 |
| author_facet |
Sucunza, D. (Diego)|||/items/c40063b2-c2e8-466b-aaa2-5a3acb7fb1f6 Rico, A.J. (Alberto J.)|||/items/7a177958-067e-4900-943e-0271d63a5021 Roda, E. (Elvira)|||/items/7ea91585-d2d9-4d11-aabf-4daab728ca1c Collantes, M. (María)|||/items/102ad3e7-3f57-4958-8e97-39af1c92626b González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac Rodriguez-Perez, A.I. (Ana I.)|||/items/4167ee59-145c-4ff4-a5ca-0482da3930fc Peñuelas-Sanchez, I. (Ivan)|||/items/7022e2fa-b3b0-48ed-8d39-2020cfae85a4 Vazquez, A. (Alfonso)|||/items/7d5cb87e-5c97-4865-aea8-a4694ef0139f Labandeira-Garcia, J.L. (José L.)|||/items/6ff85c09-f91d-4c80-bb94-2763191534eb Broccoli, V. (Vania)|||/items/5c457f7e-0f40-47a7-996e-a243054aca6c Lanciego-Pérez, J.L. (José Luis)|||/items/d2d4dbfe-4daf-4103-89ec-2ebf41b65cd1 |
| author_role |
author |
| author2 |
Rico, A.J. (Alberto J.)|||/items/7a177958-067e-4900-943e-0271d63a5021 Roda, E. (Elvira)|||/items/7ea91585-d2d9-4d11-aabf-4daab728ca1c Collantes, M. (María)|||/items/102ad3e7-3f57-4958-8e97-39af1c92626b González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac Rodriguez-Perez, A.I. (Ana I.)|||/items/4167ee59-145c-4ff4-a5ca-0482da3930fc Peñuelas-Sanchez, I. (Ivan)|||/items/7022e2fa-b3b0-48ed-8d39-2020cfae85a4 Vazquez, A. (Alfonso)|||/items/7d5cb87e-5c97-4865-aea8-a4694ef0139f Labandeira-Garcia, J.L. (José L.)|||/items/6ff85c09-f91d-4c80-bb94-2763191534eb Broccoli, V. (Vania)|||/items/5c457f7e-0f40-47a7-996e-a243054aca6c Lanciego-Pérez, J.L. (José Luis)|||/items/d2d4dbfe-4daf-4103-89ec-2ebf41b65cd1 |
| author2_role |
author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
GBA1 Parkinson’s disease Adeno-associated viral vectors Neuroprotection Synucleinopathies |
| topic |
GBA1 Parkinson’s disease Adeno-associated viral vectors Neuroprotection Synucleinopathies |
| description |
Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson's disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD-even when considering idiopathic forms of PD-has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021-01-01 2021 2021-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/114741 |
| url |
https://hdl.handle.net/10171/114741 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
MDPI |
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MDPI |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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15,811543 |