Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3
Authors:
- Daniela Cunha-GarciaDCDaniela Cunha-Garcia
- Daniela Monteiro-FernandesDMDaniela Monteiro-Fernandes
- Joana Sofia CorreiaJCJoana Sofia Correia
- Andreia Neves-CarvalhoANAndreia Neves-Carvalho
- Ana Catarina Vilaça-FerreiraAVAna Catarina Vilaça-Ferreira
- Sónia Guerra-GomesSGSónia Guerra-Gomes
- João Filipe VianaJVJoão Filipe Viana
- João Filipe OliveiraJoão Filipe Oliveira
- Andreia Teixeira-CastroAndreia Teixeira-Castro
- Patrícia MacielPatrícia Maciel
- Sara Duarte-SilvaSDSara Duarte-Silva
Open Access
- 25 June 2023
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 24 (13) , 10606
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression.Keywords
Funding Information
- Fundação para a Ciência e a Tecnologia (UIDB/50026/2020, UIDP/50026/2020, PTDC/NEUNMC/3648/2014, POCI-01-0145-FEDER-016818, 2021.08121.BD, SFRH/BD/147947/2019, SFRH/BD/140624/2018, SFRH/BPD/118779/2016, UMINHO/BIL-CNCG/2022/11, SFRH/BD/101298/2014, 2020.05109.BD, CEECIND/00685/2020, 037/18, LCF/PR/HR21/52410024, NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023)
- Fundação para a Ciência e a Tecnologia (UIDB/50026/2020, UIDP/50026/2020, PTDC/NEUNMC/3648/2014, POCI-01-0145-FEDER-016818, 2021.08121.BD, SFRH/BD/147947/2019, SFRH/BD/140624/2018, SFRH/BPD/118779/2016, UMINHO/BIL-CNCG/2022/11, SFRH/BD/101298/2014, 2020.05109.BD, CEECIND/00685/2020, 037/18, LCF/PR/HR21/52410024, NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023)
- Fundação para a Ciência e a Tecnologia (UIDB/50026/2020, UIDP/50026/2020, PTDC/NEUNMC/3648/2014, POCI-01-0145-FEDER-016818, 2021.08121.BD, SFRH/BD/147947/2019, SFRH/BD/140624/2018, SFRH/BPD/118779/2016, UMINHO/BIL-CNCG/2022/11, SFRH/BD/101298/2014, 2020.05109.BD, CEECIND/00685/2020, 037/18, LCF/PR/HR21/52410024, NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023)
- Fundação Bial (UIDB/50026/2020, UIDP/50026/2020, PTDC/NEUNMC/3648/2014, POCI-01-0145-FEDER-016818, 2021.08121.BD, SFRH/BD/147947/2019, SFRH/BD/140624/2018, SFRH/BPD/118779/2016, UMINHO/BIL-CNCG/2022/11, SFRH/BD/101298/2014, 2020.05109.BD, CEECIND/00685/2020, 037/18, LCF/PR/HR21/52410024, NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023)
- “the la Caixa” Foundation (UIDB/50026/2020, UIDP/50026/2020, PTDC/NEUNMC/3648/2014, POCI-01-0145-FEDER-016818, 2021.08121.BD, SFRH/BD/147947/2019, SFRH/BD/140624/2018, SFRH/BPD/118779/2016, UMINHO/BIL-CNCG/2022/11, SFRH/BD/101298/2014, 2020.05109.BD, CEECIND/00685/2020, 037/18, LCF/PR/HR21/52410024, NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023)
- Fundação para a Ciência e a Tecnologia (UIDB/50026/2020, UIDP/50026/2020, PTDC/NEUNMC/3648/2014, POCI-01-0145-FEDER-016818, 2021.08121.BD, SFRH/BD/147947/2019, SFRH/BD/140624/2018, SFRH/BPD/118779/2016, UMINHO/BIL-CNCG/2022/11, SFRH/BD/101298/2014, 2020.05109.BD, CEECIND/00685/2020, 037/18, LCF/PR/HR21/52410024, NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023)
- ICVS Scientific Microscopy Platform (UIDB/50026/2020, UIDP/50026/2020, PTDC/NEUNMC/3648/2014, POCI-01-0145-FEDER-016818, 2021.08121.BD, SFRH/BD/147947/2019, SFRH/BD/140624/2018, SFRH/BPD/118779/2016, UMINHO/BIL-CNCG/2022/11, SFRH/BD/101298/2014, 2020.05109.BD, CEECIND/00685/2020, 037/18, LCF/PR/HR21/52410024, NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023)
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