Loss of PINK1 causes age-dependent decrease of dopamine release and mitochondrial dysfunction

Abstract

Mutations and deletions in PTEN-induced kinase 1 (PINK1) cause autosomal recessive Parkinson's disease (PD), the second most common neurodegenerative disorder. PINK1 is a nuclear-genome encoded Ser/Thr kinase in mitochondria. PINK1 deletion was reported to affect dopamine (DA) levels in the striatum and mitochondrial functions but with conflicting results. The role of PINK1 in mitochondrial function and in PD pathogenesis remains to be elucidated thoroughly. In this study, we measured DA release using fast-scan cyclic voltammetry in acute striatal slices from both PINK1 knockout (KO) and wild-type (WT) mice at different ages. We found that single pulse-evoked DA release in the dorsal striatum of PINK1 KO mice was decreased in an age-dependent manner. Furthermore, the decrease was due to less DA release instead of an alteration of DA transporter function or DA terminal degeneration. We also found that PINK1 KO striatal slices had significantly lower basal mitochondria respiration compared to that of WT controls, and this impairment was also age-dependent. These results suggest that the impaired DA release is most likely due to mitochondrial dysfunction and lower ATP production.

PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons

“…Cortical neurons from embryonic day E16 C57BL/6 mouse or E18 Sprague Dawley rat embryos were dissected and cultured in Neurobasal media containing 2% B 27 , and 2 mM Glutamax as previously described (Van Laar et al, 2011; Dagda et al, 2014) using procedures approved by the University of Pittsburgh Institutional Animal Care and Use Committee (IACUC). For some experiments, E16 cortical neurons were derived from Pink1-/- mice (Dagda et al, 2011, 2014; Zhi et al, 2018). Human HEK293 (ATCC catalog #CRL-1573, RRID:CVCL_0045); human neuronal SH-SY5Y [parental (ATCC catalog #CRL-2266, RRID:CVCL_0019), stable PINK1-3xFLAG (#24) and stable empty vector (M14) lines (Dagda et al, 2009)]; and the mouse neuronal HT22 line used for validation of mouse RNAi (RRID:CVCL_0321), were cultured and transfected using Lipofectamine 2000 as described (Dagda et al, 2009).…”

PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

“…As compared to wild-type, dopamine from striatal slices of Pink1 KO mice decreased in an age-dependent manner. Additionally, it was found an age-dependent decrease in basal oxygen consumption rates and ATP levels in Pink1 KO mice, which suggests that decreased ATP generation may be the cause of the decreased dopamine release [ 148 ]. Recently, silencing of Pink1 in cultured mouse hippocampal neurons caused a decrease in postsynaptic density proteins PSD95 and Shank as well as glutamate receptor subunit NR2B and mGluR5.…”

Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1

“…Cellular depletion of PINK1 triggers neuronal cell death, possibly through complex interactions with several client proteins including Akt (14). PINK1 deficiency also leads to reduced dopamine levels, essential for coordinated motor function, and triggers synaptodendritic shrinkage (13,15,16) and the release of inflammatory cytokines such as TNF-α, IL-1β, and COX-2 by astrocytes and microglia, and after injury in the brain (17)(18)(19). These observations suggest that approaches that maintain or increase cellular PINK1 protein concentrations may provide important opportunities to preserve chemical energy stores during aging or stress and to Mitochondrial quality control is mediated by the PTEN-induced kinase 1 (PINK1), a cytoprotective protein that is dysregulated in inflammatory lung injury and neurodegenerative diseases.…”