Evidence map›Paper›PMID 26078453›Full record

ArticleThe Journal of biological chemistry2015

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration.

João P L Daher, Hisham A Abdelmotilib, Xianzhen Hu, Laura A Volpicelli-Daley, Mark S Moehle, Kyle B Fraser, Elie Needle, Yi Chen, Stefanus J Steyn, Paul Galatsis and 2 more

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

Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 129 papers.

0numbers the graph read from it
0cells of the map it votes in
129citing papers in PubMed
14.6field-weighted citation impact, top 1% 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

129 citing papers in PubMed, 205 citations in OpenAlex.

  1. Review
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  6. LRRK2 as a Potential Disease-Modifying Target in Sporadic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026
    Review
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  15. Genetic mutations in kinases: a comprehensive review on marketed inhibitors and unexplored targets in Parkinson's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025
    Review
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69 more citing papers are in PubMed but not listed here.

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

12 authors at 2 institutions in 1 country.

João P L DaherFrom the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Hisham A AbdelmotilibFrom the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Xianzhen HuFrom the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Laura A Volpicelli-DaleyFrom the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Mark S MoehleFrom the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Kyle B FraserFrom the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294.
Elie Needlethe Pfizer Neuroscience Research Unit, Cambridge, Massachusetts.
Yi Chenthe Pfizer Neuroscience Research Unit, Cambridge, Massachusetts.
Stefanus J SteynPfizer Pharmacokinetics, Dynamics, and Metabolism Cambridge, Cambridge, Massachusetts 02139, and.
Paul GalatsisPfizer Worldwide Medicinal Chemistry, Cambridge, Massachusetts 02139.
Warren D Hirstthe Pfizer Neuroscience Research Unit, Cambridge, Massachusetts.
Andrew B WestFrom the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, abwest@uab.edu.
University of Alabama at Birmingham · USPfizer (United States) · US

Funding

Mechanisms of LRRK2 Mediated NeurotoxicityR01NS064934 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI WEST, ANDREW B · 2010 to 2025
$6.3M
Training Program in Cell, Molecular, and Developmental BiologyT32GM008111 · NIGMS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI YODER, BRADLEY K. · 1985 to 2022
$5.4M
Role of Microglial LRRK2 in InflammationF31NS081963 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI MOEHLE, MARK S · 2012 to 2014
$87k
NIGMS NIH HHS T32 GM008111NIGMS NIH HHS T32 GM00811127NINDS NIH HHS F31 NS081963NINDS NIH HHS R01 NS064934
6 · The paper itself

Abstract

Therapeutic approaches to slow or block the progression of Parkinson disease (PD) do not exist. Genetic and biochemical studies implicate α-synuclein and leucine-rich repeat kinase 2 (LRRK2) in late-onset PD. LRRK2 kinase activity has been linked to neurodegenerative pathways. However, the therapeutic potential of LRRK2 kinase inhibitors is not clear because significant toxicities have been associated with one class of LRRK2 kinase inhibitors. Furthermore, LRRK2 kinase inhibitors have not been tested previously for efficacy in models of α-synuclein-induced neurodegeneration. To better understand the therapeutic potential of LRRK2 kinase inhibition in PD, we evaluated the tolerability and efficacy of a LRRK2 kinase inhibitor, PF-06447475, in preventing α-synuclein-induced neurodegeneration in rats. Both wild-type rats as well as transgenic G2019S-LRRK2 rats were injected intracranially with adeno-associated viral vectors expressing human α-synuclein in the substantia nigra. Rats were treated with PF-06447475 or a control compound for 4 weeks post-viral transduction. We found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of α-synuclein. Both neurodegeneration and neuroinflammation associated with G2019S-LRRK2 expression were mitigated by LRRK2 kinase inhibition. Furthermore, PF-06447475 provided neuroprotection in wild-type rats. We could not detect adverse pathological indications in the lung, kidney, or liver of rats treated with PF-06447475. These results demonstrate that pharmacological inhibition of LRRK2 is well tolerated for a 4-week period of time in rats and can counteract dopaminergic neurodegeneration caused by acute α-synuclein overexpression.

Indexed as

alpha-SynucleinAnimalsAntiparkinson AgentsDependovirusDisease Models, AnimalFemaleGene Expression RegulationGenetic VectorsHumansInjections, IntraventricularLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MaleParkinson DiseaseProtein Kinase InhibitorsProtein Serine-Threonine KinasesPyrimidines3-(4-(morpholin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl)benzonitrilealpha-SynucleinAntiparkinson AgentsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LRRK2 protein, ratProtein Kinase InhibitorsProtein Serine-Threonine KinasesPyrimidinesPyrrolesdopaminekinase inhibitorsleucine-rich repeat kinase 2 (LRRK2)neurodegenerative diseaseneuroinflammationneurorestorationα-synuclein (α-synuclein)

Identifiers

PMID26078453
PMCPMC4528108
OpenAlexW1544196343

What OpenQuestion holds

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Registered trials

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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.