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

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Abstract

The exact etiology of Parkinson’s disease (PD) remains obscure, although many cellular mechanisms including α-synuclein aggregation, oxidative damage, excessive neuroinflammation, and dopaminergic neuronal apoptosis are implicated in its pathogenesis. There is still no disease-modifying treatment for PD and the gold standard therapy, chronic use of levodopa is usually accompanied by severe side effects, mainly levodopa-induced dyskinesia (LID). Hence, the elucidation of the precise underlying molecular mechanisms is of paramount importance. Fyn is a tyrosine phospho-transferase of the Src family nonreceptor kinases that is highly implicated in immune regulation, cell proliferation and normal brain development. Accumulating preclinical evidence highlights the emerging role of Fyn in key aspects of PD and LID pathogenesis: it may regulate α-synuclein phosphorylation, oxidative stress-induced dopaminergic neuronal death, enhanced neuroinflammation and glutamate excitotoxicity by mediating key signaling pathways, such as BDNF/TrkB, PKCδ, MAPK, AMPK, NF-κB, Nrf2, and NMDAR axes. These findings suggest that therapeutic targeting of Fyn or Fyn-related pathways may represent a novel approach in PD treatment. Saracatinib, a nonselective Fyn inhibitor, has already been tested in clinical trials for Alzheimer’s disease, and novel selective Fyn inhibitors are under investigation. In this comprehensive review, we discuss recent evidence on the role of Fyn in the pathogenesis of PD and LID and provide insights on additional Fyn-related molecular mechanisms to be explored in PD and LID pathology that could aid in the development of future Fyn-targeted therapeutic approaches.

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YNP would like to acknowledge Monash University Malaysia for supporting with HDR Scholarship.

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  1. Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, 11527, Athens, Greece

    Efthalia Angelopoulou & Christina Piperi

  2. Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia

    Yam Nath Paudel & Mohd Farooq Shaikh

  3. Sheffield Teaching Hospitals, Royal Hallamshire Hospital, Glossop Rd, Broomhall, Sheffield, S10 2JF, UK

    Thomas Julian

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EA carried out the literature review, conceptualized, and prepared the initial draft. YNP and TJ edited and contributed to the final manuscript. CP provided critical inputs, edited, and contributed to the final version of the manuscript. All authors read and approved the final manuscript.

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Angelopoulou, E., Paudel, Y.N., Julian, T. et al. Pivotal Role of Fyn Kinase in Parkinson’s Disease and Levodopa-Induced Dyskinesia: a Novel Therapeutic Target?. Mol Neurobiol 58, 1372–1391 (2021). https://doi.org/10.1007/s12035-020-02201-z

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