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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—has re...

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Autores principales: Sucunza, Diego, Rico, Alberto J., Roda, Elvira, Collantes, María, González-Aseguinolaza, Gloria, Rodríguez-Pérez, Ana I., Peñuelas, Iván, Vázquez, Alfonso, Labandeira-García, José L., Broccoli, Vania, Lanciego, José L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125775/
https://www.ncbi.nlm.nih.gov/pubmed/34062940
http://dx.doi.org/10.3390/ijms22094825
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author Sucunza, Diego
Rico, Alberto J.
Roda, Elvira
Collantes, María
González-Aseguinolaza, Gloria
Rodríguez-Pérez, Ana I.
Peñuelas, Iván
Vázquez, Alfonso
Labandeira-García, José L.
Broccoli, Vania
Lanciego, José L.
author_facet Sucunza, Diego
Rico, Alberto J.
Roda, Elvira
Collantes, María
González-Aseguinolaza, Gloria
Rodríguez-Pérez, Ana I.
Peñuelas, Iván
Vázquez, Alfonso
Labandeira-García, José L.
Broccoli, Vania
Lanciego, José L.
author_sort Sucunza, Diego
collection PubMed
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.
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spelling pubmed-81257752021-05-17 Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques Sucunza, Diego Rico, Alberto J. Roda, Elvira Collantes, María González-Aseguinolaza, Gloria Rodríguez-Pérez, Ana I. Peñuelas, Iván Vázquez, Alfonso Labandeira-García, José L. Broccoli, Vania Lanciego, José L. Int J Mol Sci Article 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. MDPI 2021-05-01 /pmc/articles/PMC8125775/ /pubmed/34062940 http://dx.doi.org/10.3390/ijms22094825 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sucunza, Diego
Rico, Alberto J.
Roda, Elvira
Collantes, María
González-Aseguinolaza, Gloria
Rodríguez-Pérez, Ana I.
Peñuelas, Iván
Vázquez, Alfonso
Labandeira-García, José L.
Broccoli, Vania
Lanciego, José L.
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
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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125775/
https://www.ncbi.nlm.nih.gov/pubmed/34062940
http://dx.doi.org/10.3390/ijms22094825
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