RT Journal Article
SR Electronic
T1 Cyclin-Dependent Kinase 5 Regulates cPLA2 Activity and Neuroinflammation in Parkinson’s Disease
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0180-22.2022
DO 10.1523/ENEURO.0180-22.2022
VO 9
IS 6
A1 Paul, Sangita
A1 Fatihi, Saman
A1 Sharma, Srishti
A1 Kutum, Rintu
A1 Fields, Raymond
A1 Pant, Harish C.
A1 Thukral, Lipi
A1 BK, Binukumar
YR 2022
UL http://www.eneuro.org/content/9/6/ENEURO.0180-22.2022.abstract
AB Hyperactivation of cyclin-dependent kinase 5 (Cdk5) by p25, contributes to neuroinflammation causing neurodegeneration in Parkinson’s disease (PD) and Alzheimer’s disease. However, the mechanism by which Cdk5 induces neuroinflammation in the PD brain is largely unexplored. Here, we show that Cdk5 phosphorylates cytosolic phospholipase A2 (cPLA2) at Thr-268 and Ser-505 sites lead to its activation and generation of eicosanoid products. Mutational studies using site-directed mutagenesis and molecular simulations show that the architecture of the protein changes on each single-point mutation. Interestingly, double mutations also led to a severe decline in the activity of cPLA2 and to the disruption of its translocation to the plasma membrane. Further, the brain lysates of transgenic PD mouse models show hyperactivation of Cdk5, resulting in enhanced phosphorylation of Thr-268 and Ser-505 of cPLA2 and its heightened activity, confirming the findings observed in the cell culture model of PD. These phosphorylation sites of cPLA2 and Cdk5 could be explored as the future therapeutic targets against neuroinflammation in PD. Further, conjoint transcriptomic analysis of the publicly available human PD datasets strengthens the hypothesis that genes of the arachidonic acid, prostaglandin synthesis, and inflammatory pathways are significantly upregulated in the case of PD patients compared with that of healthy control subjects.