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.

Published on Apr 28, 2021in Frontiers in Pharmacology5.811
· DOI :10.3389/FPHAR.2021.631375
Hariharan Saminathan5
Estimated H-index: 5
,
Anamitra Ghosh19
Estimated H-index: 19
+ 5 AuthorsAnumantha G. Kanthasamy70
Estimated H-index: 70
Sources
Abstract
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 (GWAS) 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.
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#1Margherita Fabbri (University of Toulouse)H-Index: 6
#2Santiago Perez-Lloret (UBA: University of Buenos Aires)H-Index: 25
Last. Olivier RascolH-Index: 66
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To date, no drug has demonstrated clinically indisputable neuroprotective efficacy in Parkinson’s disease (PD). We also have no effective symptomatic treatment for disabling symptoms such as balanc...
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#1Hariharan Saminathan (Iowa State University)H-Index: 5
#2Adhithiya Charli (Iowa State University)H-Index: 10
Last. Arthi Kanthasamy (Iowa State University)H-Index: 59
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Abstract Systemic inflammation resulting from the release of pro-inflammatory cytokines and the chronic activation of the innate immune system remains a major cause of morbidity and mortality in the United States. After having demonstrated that Fyn, a Src family kinase, regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson's disease, we investigate here its role in modulating systemic inflammation using an endotoxic mouse model. Fyn knockout (KO) and the...
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#1Souvarish Sarkar (Iowa State University)H-Index: 14
#2Hai M. NguyenH-Index: 18
Last. Anumantha G. Kanthasamy (Iowa State University)H-Index: 70
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Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson's disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSynAgg) stimulation in primary microglial cultures and animal models of PD, as well ...
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#1Carmela Matrone (University of Naples Federico II)H-Index: 20
#2Federica Petrillo (AU: Aarhus University)H-Index: 5
Last. Gabriella Ferretti (University of Naples Federico II)H-Index: 2
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Fyn is a non-receptor or cytoplasmatic tyrosine kinase (TK) belonging to the Src family kinases (SFKs) involved in multiple transduction pathways in the central nervous system (CNS) including synaptic transmission, myelination, axon guidance, and oligodendrocyte formation. Almost one hundred years after the original description of Fyn, this protein continues to attract extreme interest because of its multiplicity of actions in the molecular signaling pathways underlying neurodevelopmental as wel...
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Summary Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated ...
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#1Kyohei Kin (Okayama University)H-Index: 6
#2Takao Yasuhara (Okayama University)H-Index: 35
Last. Isao Date (Okayama University)H-Index: 62
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Parkinson’s disease (PD) is a chronic and progressive movement disorder and the second most common neurodegenerative disease. Although many studies have been conducted, there is an unmet clinical need to develop new treatments because, currently, only symptomatic therapies are available. To achieve this goal, clarification of the pathology is required. Attempts have been made to emulate human PD and various animal models have been developed over the decades. Neurotoxin models have been commonly ...
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#1Benjamin G. Trist (USYD: University of Sydney)H-Index: 5
#2Dominic J. Hare (UTS: University of Technology, Sydney)H-Index: 44
Last. Kay L. Double (USYD: University of Sydney)H-Index: 47
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Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex...
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#1Nikhil Panicker (Iowa State University)H-Index: 14
#2Souvarish Sarkar (Iowa State University)H-Index: 14
Last. Arthi Kanthasamy (Iowa State University)H-Index: 59
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: Persistent microglia-mediated neuroinflammation is a major pathophysiological contributor to the progression of Parkinson's disease (PD), but the cell-signaling mechanisms governing chronic neuroinflammation are not well understood. Here, we show that Fyn kinase, in conjunction with the class B scavenger receptor CD36, regulates the microglial uptake of aggregated human α-synuclein (αSyn), which is the major component of PD-associated Lewy bodies. αSyn can effectively mediate LPS-independent p...
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#1Chunjuan SongH-Index: 17
#2Adhithiya Charli (Iowa State University)H-Index: 10
Last. Anumantha G. Kanthasamy (Iowa State University)H-Index: 70
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: Chronic exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). Previously, we showed that dieldrin induces dopaminergic neurotoxicity by activating a cascade of apoptotic signaling pathways in experimental models of PD. Here, we systematically investigated endosulfan's effect on the interplay between apoptosis and autophagy in dopaminergic neuronal cell models of PD. Exposing N27 dopaminergic neuronal cells to endosulfan rapidly induced autophagy, indicated b...
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#1Giovanna Cenini (University of Bonn)H-Index: 22
#2Ana Lloret (University of Valencia)H-Index: 30
Last. Roberta Cascella (UniFI: University of Florence)H-Index: 24
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Age is the main risk factor for a number of human diseases, including neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, which increasing numbers of elderly individuals suffer. These pathological conditions are characterized by progressive loss of neuron cells, compromised motor or cognitive functions, and accumulation of abnormally aggregated proteins. Mitochondrial dysfunction is one of the main features of the aging process, partic...
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Cited By1
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#1Bianca Guglietti (University of Adelaide)
#2Srisankavi Sivasankar (University of Adelaide)
Last. Lyndsey E. Collins-Praino (University of Adelaide)H-Index: 13
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Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Neurodegenerative diseases are amongst the leading cause of...
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