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Cleaved PARP antibody [E51]

RRID:AB_777102

Antibody ID

AB_777102

Target Antigen

Cleaved PARP antibody [E51] human, mouse, mouse, human

Proper Citation

(Abcam Cat# ab32064, RRID:AB_777102)

Clonality

monoclonal antibody

Comments

validation status unknown, seller recommendations provided in 2012: Flow Cyt, ICC, IHC-P, IP, WB; Immunohistochemistry; Immunohistochemistry - fixed; Western Blot; Flow Cytometry; Immunocytochemistry; Immunoprecipitation

Host Organism

rabbit

Vendor

Abcam

Cat Num

ab32064

α-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton.

  • Ordonez DG
  • Neuron
  • 2018 Jan 3

Literature context:


Abstract:

Genetics and neuropathology strongly link α-synuclein aggregation and neurotoxicity to the pathogenesis of Parkinson's disease and related α-synucleinopathies. Here we describe a new Drosophila model of α-synucleinopathy based on widespread expression of wild-type human α-synuclein, which shows robust neurodegeneration, early-onset locomotor deficits, and abundant α-synuclein aggregation. We use results of forward genetic screening and genetic analysis in our new model to demonstrate that α-synuclein expression promotes reorganization of the actin filament network and consequent mitochondrial dysfunction through altered Drp1 localization. Similar changes are present in a mouse α-synucleinopathy model and in postmortem brain tissue from patients with α-synucleinopathy. Importantly, we provide evidence that the interaction of α-synuclein with spectrin initiates pathological alteration of the actin cytoskeleton and downstream neurotoxicity. These findings suggest new therapeutic approaches for α-synuclein induced neurodegeneration.

Funding information:
  • NCI NIH HHS - U01 CA111275(United States)
  • NIA NIH HHS - R01 AG044113()
  • NICHD NIH HHS - U54 HD090255()
  • NIGMS NIH HHS - R01 GM084947()
  • NIH HHS - P40 OD018537()
  • NINDS NIH HHS - R01 NS083391()
  • NINDS NIH HHS - R01 NS086074()
  • NINDS NIH HHS - R01 NS092093()
  • NINDS NIH HHS - R01 NS098821()

Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.

  • Kolluri KK
  • Elife
  • 2018 Jan 18

Literature context:


Abstract:

Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.

Funding information:
  • Cancer Research UK - A17341()
  • NINDS NIH HHS - R01NS043915(United States)
  • Wellcome - WT097452MA()
  • Wellcome Trust - 106555/Z/14/Z()
  • Wellcome Trust - WT107963AIA()

A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo.

  • Bardai FH
  • J. Neurosci.
  • 2018 Jan 3

Literature context:


Abstract:

The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. In vitro, FTDP-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease in vivo is not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo We express wild-type human tau and five FTDP-17 mutant forms of tau in Drosophila using a site-directed insertion strategy to ensure equivalent levels of expression. We then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic animals, including analysis of both males and females. We find that FTDP-17 mutations act to enhance phosphorylation of tau and thus promote neurotoxicity in an in vivo setting. Further, we demonstrate that phosphorylation-dependent excess stabilization of the actin cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the FTDP-17 mutants tested. Finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.SIGNIFICANCE STATEMENT The microtubule protein tau aggregates and forms insoluble inclusion bodies known as neurofibrillary tangles in the brain tissue of patients with a variety of neurodegenerative disorders, including Alzheimer's disease. The tau protein is thus widely felt to play a key role in promoting neurodegeneration. However, precisely how tau becomes toxic is unclear. Here we capitalize on an "experiment of nature" in which rare missense mutations in tau cause familial neurodegeneration and neurofibrillary tangle formation. By comparing the biochemical activities of different tau mutations with their in vivo toxicity in a well controlled Drosophila model system, we find that all mutations tested increase phosphorylation of tau and trigger a cascade of neurotoxicity critically impinging on the integrity of the actin cytoskeleton.

Funding information:
  • NCRR NIH HHS - R01 RR010715(United States)
  • NICHD NIH HHS - U54 HD090255()

IRBIT controls apoptosis by interacting with the Bcl-2 homolog, Bcl2l10, and by promoting ER-mitochondria contact.

  • Bonneau B
  • Elife
  • 2016 Dec 20

Literature context:


Abstract:

IRBIT is a molecule that interacts with the inositol 1,4,5-trisphosphate (IP3)-binding pocket of the IP3 receptor (IP3R), whereas the antiapoptotic protein, Bcl2l10, binds to another part of the IP3-binding domain. Here we show that Bcl2l10 and IRBIT interact and exert an additive inhibition of IP3R in the physiological state. Moreover, we found that these proteins associate in a complex in mitochondria-associated membranes (MAMs) and that their interplay is involved in apoptosis regulation. MAMs are a hotspot for Ca2+ transfer between endoplasmic reticulum (ER) and mitochondria, and massive Ca2+ release through IP3R in mitochondria induces cell death. We found that upon apoptotic stress, IRBIT is dephosphorylated, becoming an inhibitor of Bcl2l10. Moreover, IRBIT promotes ER mitochondria contact. Our results suggest that by inhibiting Bcl2l10 activity and promoting contact between ER and mitochondria, IRBIT facilitates massive Ca2+ transfer to mitochondria and promotes apoptosis. This work then describes IRBIT as a new regulator of cell death.

Funding information:
  • Howard Hughes Medical Institute - R01 NS036715(United States)
  • NCATS NIH HHS - UL1 TR001105(United States)