PTEN‐induced Kinase 1 (PINK1) and Protein Kinase A Protects Against Mitochondrial Dysfunction and Dendritic Loss in a Toxin Model of PD (LB500)

Decreased mitochondrial and cytosolic signaling governed by serine/threonine (ser/thr) kinases, such as PINK1 and PKA, underlie the etiology of Parkinson’s disease (PD) as evidenced in PINK1 deficient neurons, toxin models of PD, and in postmortem PD brain tissue. Given that PINK1 upregulates downstream PKA signaling to remodel dendrites and enhance neuronal survival, we hypothesize that PINK1 activates distinct subcellular pools of PKA to confer neuroprotection in a chemical model of PD. Here, we demonstrate that in primary neurons, pharmacological activation of PKA signaling, overexpression of PINK1, untargeted PKA or mitochondrial PKA but not a PKA binding deficient mutant of A‐kinase anchoring protein 1 (D‐AKAP1), significantly prevents the loss of dendrites induced by 6‐hydroxydopamine (6‐OHDA). Overexpression of untargeted and mitochondrial PKA increases the basal oxygen consumption rates of SH‐SY5Y cells while only untargeted PKA protects against 6‐OHDA‐mediated decrease in mitochondrial respiration as measured by a XFE24 Analyzer. Mechanistically, PKA signaling is amplified by PINK1 by elevating the total levels of PKA monomers and enhancing the levels of membrane bound PKA. Overall, we show that PINK1 and PKA form a unique signaling axis that confers neuroprotection in the 6‐OHDA model of PD.Grant Funding Source: Supported by NIH grant P20GM103554