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

Wang, Kent Z.Q.; Steer, Erin; Otero, P. Anthony; Bateman, Nicholas W.; Cheng, Mary Hongying; Scott, Ana Lígia; Wu, Christine C.; Bahar, İvet; Shih, Yuh-Chuan; Hsueh, Yi‐Ping; Chu, Charleen T.

doi:10.1523/eneuro.0466-18.2018

Cited by 36 publications

(36 citation statements)

References 95 publications

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“…Neuritic shortening is a common pathological change in neurodegenerative diseases and has been reported in multiple PD models to include 6-OHDA, PINK1 knockdown, and mutant LRRK2 (15,30,(71)(72)(73). Here, we found that overexpression of PINK1 reversed the MPP+-induced neurite shortening, consistent with the previously reported role of PINK1 in promoting dendrite outgrowth (15,52). These pro-differentiation effects of PINK1 may be mediated through indirect activation of Akt (53) or by the ability of PINK1 to phosphorylate and activate PKA (52).…”

Section: Discussionsupporting

confidence: 91%

“…Here, we found that overexpression of PINK1 reversed the MPP+-induced neurite shortening, consistent with the previously reported role of PINK1 in promoting dendrite outgrowth (15,52). These pro-differentiation effects of PINK1 may be mediated through indirect activation of Akt (53) or by the ability of PINK1 to phosphorylate and activate PKA (52). In addition, PINK1 may influence neurite outgrowth through its effects on mitochondrial trafficking (15), as the ability to deliver mitochondria plays a limiting role in synaptogenesis (74,75).…”

Section: Discussionsupporting

confidence: 90%

“…While full-length mitochondrial PINK1 triggers Parkin-dependent mitophagy of depolarized mitochondria (8,9,(49)(50)(51), recent studies indicate that cytosolic PINK1 may have distinct functions compared to outer mitochondrial membrane-stabilized PINK1 (15). Indeed, N-terminally truncated, cytosolic PINK1 has been reported to suppress autophagy/mitophagy (14), to confer neuroprotection (8), and to promote dendrite outgrowth and neuron differentiation (15,52). These effects may be mediated through activation of Akt (53) or through activation of PKA (52), thereby promoting PKA phosphorylation of p47 (52), DRP1 (54), or LC3 (34,55) to affect neuronal growth or differentiation (52) mitochondrial fission (14) or LC3-mediated cargo targeting (56), respectively.…”

Section: Discussionmentioning

confidence: 99%

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Chronic treatment with the complex I inhibitor MPP+ depletes endogenous PTEN-induced kinase 1 (PINK1) via up-regulation of Bcl-2–associated athanogene 6 (BAG6)

Verma

Zhu

Wang

et al. 2020

Journal of Biological Chemistry

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Mitochondrial dysfunction is implicated in sporadic and familial Parkinson's disease (PD). However, the mechanisms that impair homeostatic responses to mitochondrial dysfunction remain unclear. Previously, we found that chronic, low-dose administration of the mitochondrial complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+) dysregulates mitochondrial fission–fusion, mitophagy, and mitochondrial biogenesis. Given that PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, dynamics, and turnover, we hypothesized that alterations in endogenous PINK1 levels contribute to depletion of mitochondria during chronic complex I injury. Here we found that chronic MPP+ treatment of differentiated SH-SY5Y neuronal cells significantly decreases PINK1 expression prior to reductions in other mitochondrial components. Furthermore, Bcl2-associated athanogene 6 (BAG6, BAT3, or Scythe), a protein involved in protein quality control and degradation, was highly up-regulated during the chronic MPP+ treatment. BAG6 interacted with PINK1, and BAG6 overexpression decreased the half-life of PINK1. Conversely, siRNA-mediated BAG6 knockdown prevented chronic MPP+ stress-induced loss of PINK1, reversed MPP+-provoked mitochondrial changes, increased cell viability, and prevented MPP+-induced dendrite shrinkage in primary neurons. These results indicate that BAG6 up-regulation during chronic complex I inhibition contributes to mitochondrial pathology by decreasing the levels of endogenous PINK1. Given that recessive mutations in PINK1 cause familial PD, the finding of accelerated PINK1 degradation in the chronic MPP+ model suggests that PINK1 loss of function represents a point of convergence between the neurotoxic and genetic causes of PD.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Chronic treatment with the complex I inhibitor MPP+ depletes endogenous PTEN-induced kinase 1 (PINK1) via up-regulation of Bcl-2–associated athanogene 6 (BAG6)

Verma

Zhu

Wang

et al. 2020

Journal of Biological Chemistry

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“…Parkin also indirectly interacts with cytosolic proteins, F-actin functional ARP4/5, and directly with VCP/p97 associated with mitophagy activation. PINK1 is well-known to interact with Parkin and VCP/p97, after which this complex regulates dendritic arborization [65]. Based on these results, we hypothesize that Parkin regulates organelle cross-talk potentially transferring external signals to internal platelet environments and cell-cell cross-talk among other cells.…”

Section: Discussionmentioning

confidence: 71%

Parkin Coordinates Platelet Stress Response in Diabetes Mellitus: A Big Role in a Small Cell

Lee

Hwa

et al. 2020

IJMS

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Increased platelet activation and apoptosis are characteristic of diabetic (DM) platelets, where a Parkin-dependent mitophagy serves a major endogenous protective role. We now demonstrate that Parkin is highly expressed in both healthy platelets and diabetic platelets, compared to other mitochondria-enriched tissues such as the heart, muscle, brain, and liver. Abundance of Parkin in a small, short-lived anucleate cell suggest significance in various key processes. Through proteomics we identified 127 Parkin-interacting proteins in DM platelets and compared them to healthy controls. We assessed the 11 highest covered proteins by individual IPs and confirmed seven proteins that interacted with Parkin; VCP/p97, LAMP1, HADHA, FREMT3, PDIA, ILK, and 14-3-3. Upon further STRING analysis using GO and KEGG, interactions were divided into two broad groups: targeting platelet activation through (1) actions on mitochondria and (2) actions on integrin signaling. Parkin plays an important role in mitochondrial protection through mitophagy (VCP/p97), recruiting phagophores, and targeting lysosomes (with LAMP1). Mitochondrial β-oxidation may also be regulated by the Parkin/HADHA interaction. Parkin may regulate platelet aggregation and activation through integrin signaling through interactions with proteins like FREMT3, PDIA, ILK, and 14-3-3. Thus, platelet Parkin may regulate the protection (mitophagy) and stress response (platelet activation) in DM platelets. This study identified new potential therapeutic targets for platelet mitochondrial dysfunction and hyperactivation in diabetes mellitus.

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“…Many genes with DIE have DP£ 0.5; however we also identified drastic switches (DP³0.5): Nsfl1c encodes the Nsfl1 cofactor p47, which regulates tubular ER formation, influences neuronal dendritic spine formation and dendritic arborization 37,38 . A 6nt microexon is preferentially included in HIPP across neuronal and glial cell types but is absent in the same PFC cell types (Fig 2h).…”

Section: A Gene-wise Test To Determine Differential Isoform Expressiomentioning

confidence: 87%

Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development

Joglekar

Przhibelskiy

Mahfouz

et al. 2020

Preprint

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Alternative RNA splicing varies across brain regions, but the single-cell resolution of such regional variation is unknown. Here we present the first single-cell investigation of differential isoform expression (DIE) between brain regions, by performing single cell long-read transcriptome sequencing in the mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 (www.isoformAtlas.com). Using isoform tests for brain-region specific DIE, which outperform exon-based tests, we detect hundreds of brain-region specific DIE events traceable to specific cell-types. Many DIE events correspond to functionally distinct protein isoforms, some with just a 6-nucleotide exon variant. In most instances, one cell type is responsible for brain-region specific DIE. Cell types indigenous to only one anatomic structure display distinctive DIE, where for example, the choroid plexus epithelium manifest unique transcription start sites. However, for some genes, multiple cell-types are responsible for DIE in bulk data, indicating that regional identity can, although less frequently, override cell-type specificity. We validated our findings with spatial transcriptomics and long-read sequencing, yielding the first spatially resolved splicing map in the postnatal mouse brain (www.isoformAtlas.com). Our methods are highly generalizable. They provide a robust means of quantifying isoform expression with cell-type and spatial resolution, and reveal how the brain integrates molecular and cellular complexity to serve function.

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

Abstract: Visual Abstract

Cited by 36 publications

References 95 publications

Chronic treatment with the complex I inhibitor MPP+ depletes endogenous PTEN-induced kinase 1 (PINK1) via up-regulation of Bcl-2–associated athanogene 6 (BAG6)

Chronic treatment with the complex I inhibitor MPP+ depletes endogenous PTEN-induced kinase 1 (PINK1) via up-regulation of Bcl-2–associated athanogene 6 (BAG6)

Parkin Coordinates Platelet Stress Response in Diabetes Mellitus: A Big Role in a Small Cell

Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development

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