Research

Mutations in PARK2 and PARK6 genes are responsible for the majority of hereditary Parkinson’s disease cases. These genes encode the E3 ubiquitin li...

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The Parkinson’s disease linked kinase, PINK1, is a short lived protein that undergoes cleavage upon mitochondrial import leading to its release to the cytosol and proteasomal degradation. Under mitochondria depolarising conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser65. Here we have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1 (cPINK1) in a cell line that lacks Parkin. We show that cPINK1 phosphorylates free ubiquitin and can be released to the cytosol in an active form. We show that in RPE1 cells under mitochondria depolarising conditions (i) the majority of PINK1 cleavage proceeds unimpeded and (ii) accrued PINK1 cannot be accounted for by protein stabilisation alone. Accordingly, we suggest that translation of PINK1 mRNA must be mobilised under mitochondrial depolarisation. We have further discovered a pre-conditioning phenomenon, whereby an initial depolarising treatment leaves a residual pool of active PINK1, which remains competent for seeding the activation of nascent cPINK1, despite a 16 hour recuperation period. ### Competing Interest Statement The authors have declared no competing interest.

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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.

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.

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...

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

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

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.