Evidence map›Paper›PMID 40596721›Full record

ArticleCommunications biology2025

Opposing role of phagocytic receptors MERTK and AXL in Progranulin deficient FTD.

Claire Dudley Clelland, Li Fan, Rowan Saloner, Jon Iker Etchegaray, Chad Richard Altobelli, Sally Salomonsson, Alisha M Maltos, Aradhana Sachdev, Jingjie Zhu, Se-In Lee and 19 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Communications biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
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

2 citing papers in PubMed.

  1. Article
  2. Review
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

29 authors.

Claire Dudley Clelland *Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. claire.clelland@ucsf.edu.ORCID http://orcid.org/0000-0002-9112-2278
Li Fan *Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.ORCID http://orcid.org/0000-0003-1780-6919
Rowan SalonerMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.ORCID http://orcid.org/0000-0002-1351-6183
Jon Iker EtchegarayGladstone Institutes, San Francisco, CA, USA.
Chad Richard AltobelliDepartment of Pharmaceutical Chemistry and Small Molecule Discovery Center; University of California, San Francisco, CA, USA.
Sally SalomonssonWeill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Alisha M MaltosGladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-6631-481X
Aradhana SachdevGladstone Institutes, San Francisco, CA, USA.
Jingjie ZhuHelen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Se-In LeeHelen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Yaqiao LiGladstone Institutes, San Francisco, CA, USA.
Yungui ZhouGladstone Institutes, San Francisco, CA, USA.
David LeGladstone Institutes, San Francisco, CA, USA.
Chao WangGladstone Institutes, San Francisco, CA, USA.
Gillian CarlingHelen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.ORCID http://orcid.org/0000-0002-1504-1716
Lay KodamaGladstone Institutes, San Francisco, CA, USA.
Faten SayedGladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0003-3992-4668
Jaun A Perez-BermejoGladstone Institutes, San Francisco, CA, USA.
Ethan G GeierWeill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Jennifer S YokoyamaWeill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-7274-2634
Howie RosenMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Alissa L NanaMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.ORCID http://orcid.org/0000-0003-3474-8044
Salvatore SpinaMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.ORCID http://orcid.org/0000-0003-3570-9143
Lea T GrinbergMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.ORCID http://orcid.org/0000-0002-6809-0618
William W SeeleyMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.ORCID http://orcid.org/0000-0003-1410-2027
Fanny ElahiMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Adam L BoxerMemory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Michelle R ArkinDepartment of Pharmaceutical Chemistry and Small Molecule Discovery Center; University of California, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-9366-6770
Li GanHelen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. lig2033@med.cornell.edu.ORCID http://orcid.org/0000-0003-4600-275X

Funding

Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI ADAM L. BOXER · 2019 to 2026
$120.9M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
Early Onset AD Consortium - the LEAD Study (LEADS)U01AG057195 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI APOSTOLOVA, LIANA G, CARRILLO, MARIA C · 2018 to 2023
$70.3M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
Research Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Katherine P Rankin · 2019 to 2026
$36.9M
Research Education ComponentP30AG066514 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Margaret Sewell · 2020 to 2026
$31.0M
PrPSc SPECIFIC INTERACTION WITH NOVEL PrP-Fc FUSION PROTEINSP50AG023501 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MILLER, BRUCE L · 2004 to 2018
$27.1M
Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)U01AG045390 · NIA · MAYO CLINIC ROCHESTER · PI BOEVE, BRADLEY F, ROSEN, HOWARD J · 2014 to 2018
$16.9M
Project 3: Autophagy dysfunction and neuronal activity in FTDU54NS100717 · NINDS · WEILL MEDICAL COLL OF CORNELL UNIV · PI CUERVO, ANA MARIA · 2016 to 2020
$10.8M
NRSA Training CoreTL1TR001871 · NCATS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KANAYA, ALKA M., SOMSOUK, MA · 2016 to 2025
$10.1M
Training - The Frontotemporal Lobar Degeneration Clinical Research ConsortiumU54NS092089 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BOXER, ADAM L. · 2014 to 2018
$6.4M
cGAS inhibitors for Alzheimer's disease treatmentR01AG074541 · NIA · WEILL MEDICAL COLL OF CORNELL UNIV · PI GAN, LI, SINHA, SUBHASH C · 2021 to 2025
$4.2M
NCATS NIH HHS TL1 TR001871NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG062422NIA NIH HHS P30 AG066514NIA NIH HHS P50 AG023501NIA NIH HHS R01 AG054214NIA NIH HHS R01 AG072758NIA NIH HHS R01 AG074541NIA NIH HHS U01 AG045390NIA NIH HHS U01 AG057195NIA NIH HHS U19 AG063911NIA NIH HHS U24 AG021886NIGMS NIH HHS T32 GM145460NINDS NIH HHS K08 NS112330NINDS NIH HHS U01 NS134062NINDS NIH HHS U54 NS092089NINDS NIH HHS U54 NS100717
6 · The paper itself

Abstract

Genetic mutations in the progranulin gene, GRN, cause frontotemporal dementia and a lysosomal storage disorder. Using single-nuclei RNA sequencing of the post-mortem brain tissue from adult heterozygous pathogenic granulin variant (GRN+/-) carriers we find dysregulation of microglia, phagocytosis and the phagocytic receptors MERTK and AXL. Exogenous progranulin regulates MERTK and AXL RNA expression in human microglia induced from iPSCs irrespective of GRN mutation status, without directly binding to MERTK or AXL proteins. We generated double knock-out mice and find that constitutive homozygous loss of Grn and Mertk (Grn-/-;Mertk-/-) rescued microglial disease signature while constitutive homozygous loss of Grn and Axl (Grn-/-;Axl-/-) worsened the microglial disease signature and increased lipofuscin. Lower CSF MERTK but not AXL is associated with lower progranulin levels. Furthermore, CSF MERTK is lower in symptomatic but not presymptomatic FTD patients with genetic mutations (GRN, C9ORF72, and MAPT) whereas AXL does not change between disease state and control. These data explain in part the inflammation seen in GRN-FTD and are applicable to other inflammatory states in which PGRN, MERTK and AXL play regulatory roles beyond neurodegenerative diseases. The interaction between GRN, MERTK, and AXL opens potential new therapeutic avenues to intervene on this inflammatory axis.

Indexed as

c-Mer Tyrosine KinaseFrontotemporal DementiaProgranulinsProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesAnimalsAxl Receptor Tyrosine KinaseFemaleHumansMaleMiceMice, KnockoutMicrogliaMutationPhagocytosisAXL protein, humanAxl Receptor Tyrosine KinaseAXL receptor tyrosine kinase, mousec-Mer Tyrosine KinaseGRN protein, humanMERTK protein, humanMertk protein, mouseProgranulinsProto-Oncogene ProteinsReceptor Protein-Tyrosine Kinases

Identifiers

PMID40596721
PMCPMC12218935

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.