Since PTEN-induced kinase 1 (PINK1) dysfunction is involved in the molecular genesis of PD and since our recent studies have demonstrated that the δ-opioid receptor (DOR) induced neuroprotection against hypoxic and 1-methyl-4-phenyl-pyridimium (MPP<sup>+</sup>) insults, we sought to explore whether DOR protects neuronal cells from hypoxic and/or MPP<sup>+</sup> injury via the regulation of PINK1-related pathways.
A mutation in the PINK1 gene that alters its function can increase the risk for autosomal recessive familial PD and similarly, through genetic deletion of portions of the PINK1 gene in animal models (i.e., "PINK1 knock-out (-/-) rats) produces a progressive loss of dopaminergic neurons in the substantia nigra which is analogous to the pathological hallmarks in human PD patients.
PINK1 and Parkin, two proteins that are linked to PD, play vital roles in mitophagy, which was very important in maintaining mitochondrial homeostasis.
<i>Drosophila</i> models of PD, studied for more than a decade, have helped in understanding the interaction between various genetic factors, such as <i>parkin</i> and PINK1, in this disease.
Hereditary Parkinson's disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response.
Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson's disease (PD).
These results suggest PINK1 may regulate postsynaptic plasticity in hippocampal neurons generating presymptomatic alterations in dendritic spines that eventually could lead to the neurodegeneration and cognitive decline often seen in Parkinson's disease.
The Parkinson's disease-associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation.
However, the degree to which PINK1-triggered mitophagy contributes to mitochondrial quality control in the mammalian brain, and the extent to which its disruption contributes to Parkinson's disease pathogenesis remain uncertain.
We will discuss some specific examples, including; elucidation of protein-protein interaction networks for two dominantly inherited genes, α-synuclein and leucine rich-repeat kinase 2 (LRRK2); the identification of substrates for three genes for familial PD that are also enzymes, namely LRRK2, pink1, and parkin; and changes in protein abundance that arise downstream to introduction of mutations associated with familial PD.
Then, in order to provide a mechanistic explanation for such observation, we tested the effects of Vitamin E and other alimentary antioxidants <i>in vitro</i>, by utilizing the homozygous PTEN-induced kinase 1 knockout (<i>PINK1</i><sup>-/-</sup>) mouse model of PD.
PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD.
Many of these mutations, in particular those that are found in LRRK2, DJ-1, PINK1, and Parkin, are linked to the deregulation of mRNA translation, suggesting that this process is important for the onset of PD.
Dysregulation of mitophagy, whereby damaged mitochondria are labeled for degradation by the mitochondrial kinase PINK1 and E3 ubiquitin ligase Parkin with phosphorylated ubiquitin chains (p-S65 ubiquitin), may contribute to neurodegeneration in Parkinson's disease.