Evidence map›Paper›PMID 24388974›Full record

ArticleNeurobiology of disease2014

Enhanced ubiquitin-dependent degradation by Nedd4 protects against α-synuclein accumulation and toxicity in animal models of Parkinson's disease.

Sian E Davies, Penelope J Hallett, Thomas Moens, Gaynor Smith, Emily Mangano, Hyoung Tae Kim, Alfred L Goldberg, Ji-Long Liu, Ole Isacson, George K Tofaris

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurobiology of disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
53citing papers in PubMed, 1 pooled it
3.8field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

53 citing papers in PubMed, 1 synthesis or guideline pooled it, 88 citations in OpenAlex.

  1. Pooled it
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  12. Posttranslational Modifications ofPharmacological reviews · 2024
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  15. Frontiers in molecular neuroscience · 2024
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 4 institutions in 2 countries.

Sian E DaviesNuffield Department of Clinical Neurosciences, University of Oxford, UK; Oxford Parkinson's Disease Centre, University of Oxford, UK; MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
Penelope J HallettNeuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
Thomas MoensNuffield Department of Clinical Neurosciences, University of Oxford, UK; Oxford Parkinson's Disease Centre, University of Oxford, UK.
Gaynor SmithNeuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
Emily ManganoNeuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
Hyoung Tae KimDepartment of Cell Biology, Harvard Medical School, USA.
Alfred L GoldbergDepartment of Cell Biology, Harvard Medical School, USA.
Ji-Long LiuMRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
Ole IsacsonNeuroregeneration Research Institute, McLean Hospital, Harvard Medical School, USA.
George K TofarisNuffield Department of Clinical Neurosciences, University of Oxford, UK; Oxford Parkinson's Disease Centre, University of Oxford, UK. Electronic address: george.tofaris@ndcn.ox.ac.uk.
Harvard University · USMcLean Hospital · USParkinson's UK · GBUniversity of Oxford · GB

Funding

Medical Research Council MC_U137788471Medical Research Council MC_UU_12021/3Parkinson's UK J-0901Parkinson's UK K-0819Wellcome Trust
6 · The paper itself

Abstract

Parkinson's disease is a neurodegenerative disorder, characterized by accumulation and misfolding of α-synuclein. Although the level of α-synuclein in neurons is fundamentally linked to the onset of neurodegeneration, multiple pathways have been implicated in its degradation, and it remains unclear which are the critical ubiquitination enzymes that protect against α-synuclein accumulation in vivo. The ubiquitin ligase Nedd4 targets α-synuclein to the endosomal-lysosomal pathway in cultured cells. Here we asked whether Nedd4-mediated degradation protects against α-synuclein-induced toxicity in the Drosophila and rodent models of Parkinson's disease. We show that overexpression of Nedd4 can rescue the degenerative phenotype from ectopic expression of α-synuclein in the Drosophila eye. Overexpressed Nedd4 in the Drosophila brain prevented the α-synuclein-induced locomotor defect whereas reduction in endogenous Nedd4 by RNAi led to worsening motor function and increased loss of dopaminergic neurons. Accordingly, AAV-mediated expression of wild-type but not the catalytically inactive Nedd4 decreased the α-synuclein-induced dopaminergic cell loss in the rat substantia nigra and reduced α-synuclein accumulation. Collectively, our data in two evolutionarily distant model organisms strongly suggest that Nedd4 is a modifier of α-synuclein pathobiology and thus a potential target for neuroprotective therapies.

Indexed as

alpha-SynucleinAnimalsAnimals, Genetically ModifiedBrainDopaminergic NeuronsDrosophilaEndosomal Sorting Complexes Required for TransportEyeFemaleHumansLocomotionMaleMutationNedd4 Ubiquitin Protein LigasesNerve DegenerationParkinsonian Disordersalpha-SynucleinEndosomal Sorting Complexes Required for TransportNEDD4L protein, ratNedd4 protein, humanNedd4 protein, ratNedd4 Ubiquitin Protein LigasesRNA, MessengerUbiquitin-Protein LigasesEndosomal-traffickingLysosomeProtein-degradationUbiquitination

Identifiers

PMID24388974
PMCPMC3988924
OpenAlexW2045244036

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.