Research

Parkinson’s disease (PD) is a neurodegenerative disorder with a high variability of age at onset, disease severity, and progression. This suggests that other factors, including genetic, environmental, or biological factors, are at play in PD. The loss of PINK1 causes a recessive form of PD and is typically fully penetrant; however, it features a wide range in disease onset, further supporting the existence of protective factors, endogenous or exogenous, to play a role. The loss of Pink1 in Drosophila melanogaster results in locomotion deficits, also observed in PINK1-related PD in humans. In flies, Pink1 deficiency induces defects in the ability to fly; nonetheless, around ten percent of the mutant flies are still capable of flying, indicating that advantageous factors affecting penetrance also exist in flies. Here, we aimed to identify the mechanisms underlying this reduced penetrance in Pink1-deficient flies. We performed genetic screening in pink1-mutant flies to identify RNA expression alterations affecting the flying ability. The most important biological processes involved were transcriptional and translational activities, endoplasmic reticulum (ER) regulation, and flagellated movement and microtubule organization. We validated two ER-related proteins, zonda and windbeutel, to positively affect the flying ability of Pink1-deficient flies. Thus, our data suggest that these processes are involved in the reduced penetrance and that influencing them may be beneficial for Pink1 deficiency.

Mutations in parkin and phosphatase and tensin homolog–induced putative kinase 1 (PINK1) are individually associated with recessive familial forms of Parkinson disease (PD). Parkin is an E3 ligase that promotes ubiquitination of a number of substrates, including itself. In Drosophila, parkin plays...

Mitophagy is crucial for mitochondrial quality control and maintenance of cellular homeostasis. Here the authors identify an E3 ubiquitin ligase, HUWE1, that collaborates with LC3-interacting protein AMBRA1 to induce mitochondrial clearance.

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PINK1 Antibody (38CT20.8.5): sc-517353

npj Parkinson's Disease - Upregulated ECM genes and increased synaptic activity in Parkinson’s human DA neurons with PINK1/ PRKN mutations

Crystal structure of the cytosolic domain of Tribolium castaneum PINK1 phosphorylated at Ser205 in complex with ADP analog

Crystal structure of the cytosolic domain of Tribolium castaneum PINK1 phosphorylated at Ser205 in complex with ADP analog

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The protein kinase PINK1 was recently shown to phosphorylate ubiquitin (Ub) on Ser65, and phosphoUb activates the E3 ligase Parkin allosterically. Here, we show that PINK1 can phosphorylate every Ub in Ub chains. Moreover, Ser65 phosphorylation alters Ub structure, generating two conformations in solution. A crystal structure of the major conformation resembles Ub but has altered surface properties. NMR reveals a second phosphoUb conformation in which β5‐strand slippage retracts the C‐terminal tail by two residues into the Ub core. We further show that phosphoUb has no effect on E1‐mediated E2 charging but can affect discharging of E2 enzymes to form polyUb chains. Notably, UBE2R1‐ (CDC34), UBE2N/UBE2V1‐ (UBC13/UEV1A), TRAF6‐ and HOIP‐mediated chain assembly is inhibited by phosphoUb. While Lys63‐linked poly‐phosphoUb is recognized by the TAB2 NZF Ub binding domain (UBD), 10 out of 12 deubiquitinases (DUBs), including USP8, USP15 and USP30, are impaired in hydrolyzing phosphoUb chains. Hence, Ub phosphorylation has repercussions for ubiquitination and deubiquitination cascades beyond Parkin activation and may provide an independent layer of regulation in the Ub system.

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GLP-1 analogs are widely used to treat patients with type 2 diabetes in recent years. Studies have found that GLP-1 analogs have multiple organ benefits. How...

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Cell Research - CRISPR/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys

The main neuropathological hallmarks of Parkinson’s disease (PD) are loss of dopaminergic neurons in the substantia nigra and intraneuronal protein ag…

Background Cancer cells can modulate the expression of many proteins that are essential for supporting their uncontrolled proliferation. Heat shock protein 90 (HSP90) is ubiquitously expressed in most cell types and participates in controlling many survival pathways. Cancer cells utilize HSP90 in order to prolong their survival, thus they tend to overexpress it. Based on its importance for cancer cells, we aim to investigate the molecular mechanisms that link HSP90 inhibition in colon cancer cells with oxidative stress and mitochondrial stress—related regulators. Materials and methods We used RKO colon cancer cells, blocking HSP90 with the inhibitor AT13387 and HSP90 siRNA. Cell proliferation and apoptosis were measured via CCK8 ELISA and Fluorescent Apoptosis Assays. Western blotting and immunocytochemistry assessed oxidative and mitochondrial stress markers BNIP3, PINK1, GP91/NOX2, and IRE1α in treated cells. Results Our findings reveal that inhibiting HSP90 with AT13387 reduces RKO cell viability by suppressing proliferation and enhancing Annexin-V expression, indicative of increased apoptosis. This rise in apoptosis is associated with PINK1 downregulation and BNIP3 upregulation, markers of mitochondrial dysfunction and oxidative stress, respectively. Additionally, AT13387 treatment elevated the protein level of GP91, a marker of oxidative stress, and IRE1α, a marker of ER stress. Similarly, genetic knockdown of HSP90 in RKO cells produced comparable effects, including reduced cell survival and a decreased PINK1/BNIP3 ratio. Conclusion Targeting HSP90 in colon cancer cells disrupts their survival by decreasing PINK1 and increasing BNIP3, which activates oxidative and endoplasmic reticulum stress, ultimately triggering apoptosis.

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Cell Death & Differentiation - Analysis of neuronal phosphoproteome reveals PINK1 regulation of BAD function and cell death

J. Neurochem. (2011) 117, 856–867. Abstract Intramembrane proteolysis is a conserved mechanism that regulates a variety of cellular processes ranging from transcription control to signaling. In m...