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 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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by disabling motor deficits such as resting tremor, muscular rigidity, scarce voluntary movements and postural instability (Poewe et al, 2017; Elkouzi et al, 2019)
We report that 1) Fyn was highly expressed in nigral DAergic neurons; 2) suppression of Fyn by tyrosine kinase inhibitor or RNAi-mediated knockdown (KD) attenuated PKCδ Y311 phosphorylation and its proteolytic activation as well as DAergic neuronal apoptosis; and 3) Fyn KO mice were significantly protected from MPTP-induced DAergic degeneration and locomotor deficits, thereby providing overall credence to the premise that Fyn could serve as a novel pharmacological target of PD
Since the activation time points of Fyn kinase and PKCδ Y311 phosphorylation coincided, we investigated the functional roles of Fyn activation and Y311-dependent proteolytic activation of PKCδ during MPP+-induced DAergic cell death
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by disabling motor deficits such as resting tremor, muscular rigidity, scarce voluntary movements and postural instability (Poewe et al, 2017; Elkouzi et al, 2019). DA replacement therapy using levodopa remains the gold standard for symptomatic relief in PD patients. Due to the well-documented limitations of long-term DA replacement therapy and its widespread debilitating side-effects, neuroprotective strategies that slow or halt the disease progression are urgently needed (Simuni et al, 2009a; Simuni et al, 2009b; Sarkar et al, 2016; Fabbri et al, 2020). Mitochondrial dysfunction, oxidative stress, neuroinflammation and impaired protein degradation are implicated as potential pathological mechanisms of PD, but key downstream signaling targets contributing to nigral dopaminergic neuronal degeneration are not well established. The identification of potential pharmacological targets has been actively explored in PD
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