Pivotal Role of Fyn Kinase in Parkinson’s Disease and Levodopa-Induced Dyskinesia: a Novel Therapeutic Target?

Angelopoulou, Efthalia; Paudel, Yam Nath; Julian, Thomas; Shaikh, Mohd Farooq; Piperi, Christina

doi:10.1007/s12035-020-02201-z

Cited by 21 publications

(19 citation statements)

References 135 publications

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“…GSK-3β, FYN, and DYRK1A represent three closely related PKs widely investigated within the neurokinome context due to their pivotal roles in both the onset and development of complex CNS-related diseases, including neurodegenerative (e.g., AD, Pick's disease (PiD), frontotemporal lobar degeneration (FTLD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS)) and neuromuscular disorders (e.g., spinal muscular atrophy (SMA) and myotonic dystrophy type 1 (DM1)) [19][20][21][22][23][24][25][26]. Despite the different clinical manifestations, common pathogenic mechanisms, including oxidative stress, abnormal protein deposition, mitochondrial deficit, glutamate excitotoxicity, and neuroinflammation have been observed, pointing to converging pathways in neurodegeneration [27,28].…”

Section: Gsk-3β Fyn and Dyrk1a Emerging Targets In The Neurokinomementioning

confidence: 99%

“…Three different FYN isoforms have been identified: FYN-B is mainly expressed in the CNS, FYN-T is mainly expressed in hematopoietic cells (T-cells), and FYN-Delta7 is mainly expressed in peripheral blood mononuclear cells [42]. As all SFK members, the FYN structure is characterized by six different domains [24,43,44]: the Src homology (SH) domains SH1 (catalytic domain), SH2, SH3, SH4, the so-called unique domain, and a C-terminal regulatory region (Figure 4). All FYN isoforms share the catalytic domain SH1; however, FYN-B and FYN-T differ in the linker sequence between SH1 and SH2, while FYN-Delta7 presents a deletion of residues 233-287 when compared to FYN-B [42,45].…”

Section: Fynmentioning

confidence: 99%

“…However, it has been demonstrated in microglial cell lines treated with aggregated α-syn, which may induce FYN downregulation at the transcriptional level as a compensatory negative feedback loop, potentially "aiming" to protect the cell against FYN overactivation. Nevertheless, the final effects of FYN-mediated α-syn phosphorylation has yet to be elucidated [24,86].…”

Section: α-Syn Phosphorylationmentioning

confidence: 99%

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GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Demuro

Martino

Ortega

et al. 2021

IJMS

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Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties.

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Section: Gsk-3β Fyn and Dyrk1a Emerging Targets In The Neurokinomementioning

confidence: 99%

Section: Fynmentioning

confidence: 99%

Section: α-Syn Phosphorylationmentioning

confidence: 99%

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GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Demuro

Martino

Ortega

et al. 2021

IJMS

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“…These results could suggest impaired tyrosine phosphorylation in Parkinson's disease due to increased STEP. However, the role of Fyn in Parkinson's disease is generally thought to be negative, and potential therapeutic interest of its inhibitors has been proposed [see (Angelopoulou et al, 2020) for a recent review].…”

Section: Parkinson's Diseasementioning

confidence: 99%

The Non-receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases

Pins

Mendes

Giralt

et al. 2021

Front. Synaptic Neurosci.

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Pyk2 is a non-receptor tyrosine kinase highly enriched in forebrain neurons. Pyk2 is closely related to focal adhesion kinase (FAK), which plays an important role in sensing cell contacts with extracellular matrix and other extracellular signals controlling adhesion and survival. Pyk2 shares some of FAK’s characteristics including recruitment of Src-family kinases after autophosphorylation, scaffolding by interacting with multiple partners, and activation of downstream signaling pathways. Pyk2, however, has the unique property to respond to increases in intracellular free Ca2+, which triggers its autophosphorylation following stimulation of various receptors including glutamate NMDA receptors. Pyk2 is dephosphorylated by the striatal-enriched phosphatase (STEP) that is highly expressed in the same neuronal populations. Pyk2 localization in neurons is dynamic, and altered following stimulation, with post-synaptic and nuclear enrichment. As a signaling protein Pyk2 is involved in multiple pathways resulting in sometimes opposing functions depending on experimental models. Thus Pyk2 has a dual role on neurites and dendritic spines. With Src family kinases Pyk2 participates in postsynaptic regulations including of NMDA receptors and is necessary for specific types of synaptic plasticity and spatial memory tasks. The diverse functions of Pyk2 are also illustrated by its role in pathology. Pyk2 is activated following epileptic seizures or ischemia-reperfusion and may contribute to the consequences of these insults whereas Pyk2 deficit may contribute to the hippocampal phenotype of Huntington’s disease. Pyk2 gene, PTK2B, is associated with the risk for late-onset Alzheimer’s disease. Studies of underlying mechanisms indicate a complex contribution with involvement in amyloid toxicity and tauopathy, combined with possible functional deficits in neurons and contribution in microglia. A role of Pyk2 has also been proposed in stress-induced depression and cocaine addiction. Pyk2 is also important for the mobility of astrocytes and glioblastoma cells. The implication of Pyk2 in various pathological conditions supports its potential interest for therapeutic interventions. This is possible through molecules inhibiting its activity or increasing it through inhibition of STEP or other means, depending on a precise evaluation of the balance between positive and negative consequences of Pyk2 actions.

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“…Fyn also plays a critical role in both peripheral and central inflammatory processes (Nygaard et al, 2014). This has led to speculation Fyn dysregulation may be implicated in the pathophysiology of multiple neurodegenerative diseases, including PD (Angelopoulou et al, 2021;Moore et al, 2002;Panicker et al, 2015;Stuart et al, 2007). In support of this, a seminal study by Panicker and colleagues in both cell culture and animal models of PD, described the critical role of Fyn in regulating the microglial-mediated inflammatory response through nuclear translocation of the p65 component of NFκß into the nucleus and subsequent up-regulation of pro-inflammatory cytokine production (Panicker et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Fyn kinase inhibition using AZD0530 improves recognition memory and reduces depressive-like behaviour in an experimental model of Parkinson’s disease

Carr

Ellul

et al. 2021

Preprint

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Fyn kinase has recently been established as a major upstream regulator of neuroinflammation in PD. This study aimed to determine if inhibition of Fyn kinase could lead to reduced neuroinflammation and improvements in motor and non-motor impairments in an early-stage model of PD. An experimental model of PD was produced using intra-striatal injection (4ul) of the neurotoxin 6-OHDA (5ug/ul). Sprague Dawley rats (n=42) were given either vehicle, 6mg/kg or 12mg/kg of Fyn kinase inhibitor (AZD0530) daily for 32 days via oral gavage and tested on a battery of tasks assessing motor, cognitive and neuropsychiatric outcomes. AZD 0530 administration led to improvement in volitional locomotion and recognition memory, as well as a reduction in depressive-like behaviour. Pathologically, an inflammatory response was observed; however, there were no significant differences in markers of neuroinflammation between treatment groups. Taken together, results indicate a potential therapeutic benefit for use of Fyn kinase inhibition to treat non-motor symptoms of PD, although mechanisms remain to be elucidated.

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Pivotal Role of Fyn Kinase in Parkinson’s Disease and Levodopa-Induced Dyskinesia: a Novel Therapeutic Target?

Cited by 21 publications

References 135 publications

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

The Non-receptor Tyrosine Kinase Pyk2 in Brain Function and Neurological and Psychiatric Diseases

Fyn kinase inhibition using AZD0530 improves recognition memory and reduces depressive-like behaviour in an experimental model of Parkinson’s disease

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