Evidence map›Paper›PMID 34344440›Full record

ArticleMolecular neurodegeneration2021

Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration.

Swetha Mohan, Paul J Sampognaro, Andrea R Argouarch, Jason C Maynard, Mackenzie Welch, Anand Patwardhan, Emma C Courtney, Jiasheng Zhang, Amanda Mason, Kathy H Li and 6 more

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

Article in Molecular neurodegeneration, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed
5.1field-weighted citation impact, top 4% 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

25 citing papers in PubMed, 51 citations in OpenAlex.

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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 1 institution in 1 country.

Swetha MohanDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Paul J SampognaroDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Andrea R ArgouarchDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Jason C MaynardDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California, 94143, USA.
Mackenzie WelchDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Anand PatwardhanDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Emma C CourtneyDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Jiasheng ZhangDepartment of Pathology, University of California, San Francisco, California, 94143, USA.
Amanda MasonDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Kathy H LiDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California, 94143, USA.
Eric J HuangDepartment of Pathology, University of California, San Francisco, California, 94143, USA.
William W SeeleyDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Bruce L MillerDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA.
Alma BurlingameDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California, 94143, USA.
Mathew P JacobsonDepartment of Pharmaceutical Chemistry, University of California, San Francisco, California, 94143, USA.
Aimee W KaoDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, California, 94143, USA. aimee.kao@ucsf.edu.ORCID 0000-0002-7686-7968
University of California, San Francisco · US

Funding

TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6M
PrPSc SPECIFIC INTERACTION WITH NOVEL PrP-Fc FUSION PROTEINSP50AG023501 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MILLER, BRUCE L · 2004 to 2018
$27.1M
Understanding the molecular functions of progranulin and granulin in FTLDR01NS095257 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAO, AIMEE · 2015 to 2019
$1.9M
Understanding cleaved granulin production, protease inhibition and effects on protein homeostasisR01AG059052 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAO, AIMEE · 2018 to 2022
$1.8M
NIA NIH HHS P01 AG019724NIA NIH HHS P50 AG023501NIA NIH HHS R01 AG059052NIGMS NIH HHS T32 GM007618NINDS NIH HHS R01 NS095257
6 · The paper itself

Abstract

backgroundProgranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP-Pgrn). Progranulin (PGRN) is an intracellular and secreted pro-protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP-Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments. Therefore, to better understand the conversion of intracellular PGRN into granulins, we systematically tested the ability of different classes of endo-lysosomal proteases to process PGRN at a range of pH setpoints.

resultsIn vitro cleavage assays identified multiple enzymes that can process human PGRN into multi- and single-granulin fragments in a pH-dependent manner. We confirmed the role of cathepsin B and cathepsin L in PGRN processing and showed that these and several previously unidentified lysosomal proteases (cathepsins E, G, K, S and V) are able to process PGRN in distinctive, pH-dependent manners. In addition, we have demonstrated a new role for asparagine endopeptidase (AEP) in processing PGRN, with AEP having the unique ability to liberate granulin F from the pro-protein. Brain tissue from individuals with FTLD-TDP-Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease.

conclusionsThis study demonstrates that multiple lysosomal proteases may work in concert to liberate multi-granulin fragments and granulins. It also implicates both AEP and granulin F in the neurobiology of FTLD-TDP-Pgrn. Modulating progranulin cleavage and granulin production may represent therapeutic strategies for FTLD-Pgrn and other progranulin-related diseases.

Indexed as

Cell LineFrontotemporal Lobar DegenerationGranulinsHumansLysosomesNeuronsPeptide HydrolasesProgranulinsGranulinsGRN protein, humanPeptide HydrolasesProgranulinsAsparagine endopeptidaseFrontotemporal lobar degenerationGranulinLysosomepHProgranulinProtease

Identifiers

PMID34344440
PMCPMC8330050
OpenAlexW3115683357

What OpenQuestion holds

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LicenceCC BY
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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.