We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3).
The Parkinson's disease (PD)-related ubiquitin ligase Parkin and mitochondrial kinase PINK1 function together in the clearance of damaged mitochondria.
The Parkinson disease-associated proteins PINK1 and PRKN coordinate the ubiquitination of mitochondrial outer membrane proteins to tag them either for degradation or for autophagic clearance of the mitochondrion.
NCLX inhibition has been described in a familial form of Parkinson's disease where PINK-1 deficiency leads to a delayed calcium efflux and mitochondrial Ca<sup>2+</sup> overload in response to physiological Ca<sup>2+</sup> stimulation.
Our findings suggest a novel pathway by which PINK1 phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis and implicate the dysregulation of this mitochondrial pathway in PD pathogenesis.
Loss-of-function of PINK1/Parkin-mediated mitophagy results in the accumulation of dysfunctional mitochondria, which could be one etiology of Parkinson's disease (PD).
However, in a large Saudi family with PD with at least 3 consanguineous marriages between first cousins, we detected a threonine to methionine substitution at codon 313 (T313M) PINK1 mutation that affected the kinase domain.
Here we investigated the effect of supplementing grape skin extract (GSE) left from red wine-production process to the daily food intake of a Drosophila melanogaster model of Parkinson's disease (PD) associated with PTEN-induced kinase 1 (PINK1) loss-of-function.
Proapoptotic activity of IPAS is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of Parkinson's disease.
This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.
Pharmacologic agents capable of increasing kinase function would be useful for treating diseases associated with reduced kinase activity, such as inherited forms of Parkinson's disease.In this issue, Hertz et al. report an innovative approach for activating the Parkinson's-associated kinase PINK1 in cells with an ATP-derived neo-substrate.
We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD.
Taken together, these results suggest a unique pathogenic mechanism of PINK1PD: The loss of PINK1 impairs mitochondrial fission, which causes defective assembly of the ETC complexes, leading to abnormal bioenergetics.
Moreover, an observed decrease in norepinephrine concentrations in the LC is consistent with the hypothesis that early-stage PD includes noradrenergic loss in the brainstem, and is congruent with a significant increase in catechol-O-methyltransferase expression in the LC of Pink1 -/- animals.
Mutations in the genes PTEN-induced putative kinase 1 (PINK1), PARKIN,and DJ-1 cause autosomal recessive forms of Parkinson disease (PD), and the Pink1/Parkin pathway regulates mitochondrial integrity and function.An important question is whether the proteins encoded by these genes function to regulate activities of other cellular compartments.
Recent observations in Drosophila have provided important insights into the cellular basis of PD pathogenesis through the demonstration that two genes associated with familial forms of PD, pink1 and parkin, function in a common pathway.
We have exploited our recent discovery that recombinant insect PINK1 is catalytically active to test whether PINK1 directly phosphorylates 15 proteins encoded by PD-associated genes as well as proteins reported to bind PINK1.