Pivotal Role of Fyn Kinase in Parkinson's Disease and Levodopa-Induced Dyskinesia: a Novel Therapeutic Target?
Efthalia AngelopoulouYam Nath PaudelThomas JulianMohd Farooq ShaikhChristina PiperiPublished in: Molecular neurobiology (2020)
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.
Keyphrases
- signaling pathway
- oxidative stress
- clinical trial
- cell proliferation
- parkinson disease
- pi k akt
- drug induced
- cerebral ischemia
- traumatic brain injury
- deep brain stimulation
- protein kinase
- high glucose
- tyrosine kinase
- randomized controlled trial
- epithelial mesenchymal transition
- nuclear factor
- endothelial cells
- bone marrow
- lipopolysaccharide induced
- cell cycle
- stem cells
- current status
- body mass index
- immune response
- physical activity
- weight gain
- molecular dynamics
- stress induced
- toll like receptor
- drug delivery
- density functional theory
- study protocol
- placebo controlled
- replacement therapy