Evidence map›Paper›PMID 30594931›Full record

ArticleJournal of Huntington's disease2019

Rac1 Activity Is Modulated by Huntingtin and Dysregulated in Models of Huntington's Disease.

Adelaide Tousley, Maria Iuliano, Elizabeth Weisman, Ellen Sapp, Ningzhe Zhang, Petr Vodicka, Jonathan Alexander, Hubert Aviolat, Leah Gatune, Patrick Reeves and 6 more

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

Article in Journal of Huntington's disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
1.5field-weighted citation impact, top 19% 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

15 citing papers in PubMed, 31 citations in OpenAlex.

  1. Article
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  4. Huntingtin Interacting Proteins and Pathological Implications.International journal of molecular sciences · 2023
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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

16 authors at 3 institutions in 1 country.

Adelaide TousleyDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Maria IulianoDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Elizabeth WeismanDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Ellen SappDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Ningzhe ZhangBuck Institute for Research on Aging, Novato, CA, USA.
Petr VodickaDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Jonathan AlexanderDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Hubert AviolatDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Leah GatuneDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Patrick ReevesDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Xueyi LiDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Anastasia KhvorovaRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Lisa M EllerbyBuck Institute for Research on Aging, Novato, CA, USA.
Neil AroninRNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Marian DiFigliaDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Kimberly B Kegel-GleasonDepartment of Neurology, Laboratory of Cellular Neurobiology, Massachusetts General Hospital, Charlestown, MA, USA.
Massachusetts General Hospital · USBuck Institute for Research on Aging · USUniversity of Massachusetts Chan Medical School · US

Funding

Identifying Factors Regulating Medium Spiny Neuron Differentiation or Maintenance as Therapeutic Targets for Huntington's Disease using Induced Pluripotent Stem CellsR01NS100529 · NINDS · BUCK INSTITUTE FOR RESEARCH ON AGING · PI Lisa M Ellerby · 2016 to 2026
$5.6M
Mid-Scale RNA Synthesis, Purification and Quality Control SystemS10OD020012 · OD · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI KHVOROVA, ANASTASIA · 2015 to 2015
$563k
NIH HHS S10 OD020012NINDS NIH HHS R01 NS100529
6 · The paper itself

Abstract

backgroundPrevious studies suggest that Huntingtin, the protein mutated in Huntington's disease (HD), is required for actin based changes in cell morphology, and undergoes stimulus induced targeting to plasma membranes where it interacts with phospholipids involved in cell signaling. The small GTPase Rac1 is a downstream target of growth factor stimulation and PI 3-kinase activity and is critical for actin dependent membrane remodeling.

objectiveTo determine if Rac1 activity is impaired in HD or regulated by normal Huntingtin.

methodsAnalyses were performed in differentiated control and HD human stem cells and HD Q140/Q140 knock-in mice. Biochemical methods included SDS-PAGE, western blot, immunoprecipitation, affinity chromatography, and ELISA based Rac activity assays.

resultsBasal Rac1 activity increased following depletion of Huntingtin with Huntingtin specific siRNA in human primary fibroblasts and in human control neuron cultures. Human cells (fibroblasts, neural stem cells, and neurons) with the HD mutation failed to increase Rac1 activity in response to growth factors. Rac1 activity levels were elevated in striatum of 1.5-month-old HD Q140/Q140 mice and in primary embryonic cortical neurons from HD mice. Affinity chromatography analysis of striatal lysates showed that Huntingtin is in a complex with Rac1, p85α subunit of PI 3-kinase, and the actin bundling protein α-actinin and interacts preferentially with the GTP bound form of Rac1. The HD mutation reduced Huntingtin interaction with p85α.

conclusionsThese findings suggest that Huntingtin regulates Rac1 activity as part of a coordinated response to growth factor signaling and this function is impaired early in HD.

Indexed as

AnimalsCell DifferentiationCorpus StriatumDisease Models, AnimalHumansHuntingtin ProteinHuntington DiseaseMiceMicrofilament ProteinsMutationNerve Tissue ProteinsNeuronsNeuropeptidesrac1 GTP-Binding ProteinSignal TransductionHTT protein, humanHuntingtin ProteinMicrofilament ProteinsNerve Tissue ProteinsNeuropeptidesrac1 GTP-Binding ProteinRAC1 protein, humanRac1 protein, mouseActingrowth factorGTPaseHTTPI 3-kinase“Ras-Related C3 Botulinum Toxin Substrate 1”signaling

Identifiers

PMID30594931
PMCPMC6398565
OpenAlexW2908114854

What OpenQuestion holds

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LicenceCC BY-NC
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.