Cargando…
Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease
Oxidative stress, neuroinflammation and apoptosis are some of the key etiological factors responsible for dopamin(DA)ergic degeneration during Parkinson’s disease (PD), yet the downstream molecular mechanisms underlying neurodegeneration are largely unknown. Recently, a genome-wide association study...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113680/ https://www.ncbi.nlm.nih.gov/pubmed/33995031 http://dx.doi.org/10.3389/fphar.2021.631375 |
_version_ | 1783690913409662976 |
---|---|
author | Saminathan, Hariharan Ghosh, Anamitra Zhang, Danhui Song, Chunjuan Jin, Huajun Anantharam, Vellareddy Kanthasamy, Arthi Kanthasamy, Anumantha G. |
author_facet | Saminathan, Hariharan Ghosh, Anamitra Zhang, Danhui Song, Chunjuan Jin, Huajun Anantharam, Vellareddy Kanthasamy, Arthi Kanthasamy, Anumantha G. |
author_sort | Saminathan, Hariharan |
collection | PubMed |
description | Oxidative stress, neuroinflammation and apoptosis are some of the key etiological factors responsible for dopamin(DA)ergic degeneration during Parkinson’s disease (PD), yet the downstream molecular mechanisms underlying neurodegeneration are largely unknown. Recently, a genome-wide association study revealed the FYN gene to be associated with PD, suggesting that Fyn kinase could be a pharmacological target for PD. In this study, we report that Fyn-mediated PKCδ tyrosine (Y311) phosphorylation is a key event preceding its proteolytic activation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinsonism. MPP(+)/MPTP induced Fyn kinase activation in N27 DAergic neuronal cells and the mouse substantia nigra. PKCδ-Y311 phosphorylation by activated Fyn initiates the apoptotic caspase-signaling cascade during DAergic degeneration. Pharmacological attenuation of Fyn activity protected DAergic neurons from MPP(+)-induced degeneration in primary mesencephalic neuronal cultures. We further employed Fyn wild-type and Fyn knockout (KO) mice to confirm whether Fyn is a valid pharmacological target of DAergic neurodegeneration. Primary mesencephalic neurons from Fyn KO mice were greatly protected from MPP(+)-induced DAergic cell death, neurite loss and DA reuptake loss. Furthermore, Fyn KO mice were significantly protected from MPTP-induced PKCδ-Y311 phosphorylation, behavioral deficits and nigral DAergic degeneration. This study thus unveils a mechanism by which Fyn regulates PKCδ′s pro-apoptotic function and DAergic degeneration. Pharmacological inhibitors directed at Fyn activation could prove to be a novel therapeutic target in the delay or halting of selective DAergic degeneration during PD. |
format | Online Article Text |
id | pubmed-8113680 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81136802021-05-13 Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease Saminathan, Hariharan Ghosh, Anamitra Zhang, Danhui Song, Chunjuan Jin, Huajun Anantharam, Vellareddy Kanthasamy, Arthi Kanthasamy, Anumantha G. Front Pharmacol Pharmacology Oxidative stress, neuroinflammation and apoptosis are some of the key etiological factors responsible for dopamin(DA)ergic degeneration during Parkinson’s disease (PD), yet the downstream molecular mechanisms underlying neurodegeneration are largely unknown. Recently, a genome-wide association study revealed the FYN gene to be associated with PD, suggesting that Fyn kinase could be a pharmacological target for PD. In this study, we report that Fyn-mediated PKCδ tyrosine (Y311) phosphorylation is a key event preceding its proteolytic activation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinsonism. MPP(+)/MPTP induced Fyn kinase activation in N27 DAergic neuronal cells and the mouse substantia nigra. PKCδ-Y311 phosphorylation by activated Fyn initiates the apoptotic caspase-signaling cascade during DAergic degeneration. Pharmacological attenuation of Fyn activity protected DAergic neurons from MPP(+)-induced degeneration in primary mesencephalic neuronal cultures. We further employed Fyn wild-type and Fyn knockout (KO) mice to confirm whether Fyn is a valid pharmacological target of DAergic neurodegeneration. Primary mesencephalic neurons from Fyn KO mice were greatly protected from MPP(+)-induced DAergic cell death, neurite loss and DA reuptake loss. Furthermore, Fyn KO mice were significantly protected from MPTP-induced PKCδ-Y311 phosphorylation, behavioral deficits and nigral DAergic degeneration. This study thus unveils a mechanism by which Fyn regulates PKCδ′s pro-apoptotic function and DAergic degeneration. Pharmacological inhibitors directed at Fyn activation could prove to be a novel therapeutic target in the delay or halting of selective DAergic degeneration during PD. Frontiers Media S.A. 2021-04-28 /pmc/articles/PMC8113680/ /pubmed/33995031 http://dx.doi.org/10.3389/fphar.2021.631375 Text en Copyright © 2021 Saminathan, Ghosh, Zhang, Song, Jin, Anantharam, Kanthasamy and Kanthasamy. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Saminathan, Hariharan Ghosh, Anamitra Zhang, Danhui Song, Chunjuan Jin, Huajun Anantharam, Vellareddy Kanthasamy, Arthi Kanthasamy, Anumantha G. Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease |
title | Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease |
title_full | Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease |
title_fullStr | Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease |
title_full_unstemmed | Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease |
title_short | Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease |
title_sort | fyn kinase-mediated pkcδ y311 phosphorylation induces dopaminergic degeneration in cell culture and animal models: implications for the identification of a new pharmacological target for parkinson’s disease |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113680/ https://www.ncbi.nlm.nih.gov/pubmed/33995031 http://dx.doi.org/10.3389/fphar.2021.631375 |
work_keys_str_mv | AT saminathanhariharan fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease AT ghoshanamitra fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease AT zhangdanhui fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease AT songchunjuan fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease AT jinhuajun fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease AT anantharamvellareddy fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease AT kanthasamyarthi fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease AT kanthasamyanumanthag fynkinasemediatedpkcdy311phosphorylationinducesdopaminergicdegenerationincellcultureandanimalmodelsimplicationsfortheidentificationofanewpharmacologicaltargetforparkinsonsdisease |