Evidence map›Paper›PMID 41572567›Full record

ArticleJournal of neurochemistry2026

Prosaposin Is Cleaved Into Saposins by Multiple Cathepsins in a Progranulin-Regulated Fashion.

Molly Hodul, Courtney Lane-Donovan, Emily S Cheang, Vienna Gao, Paul J Sampognaro, Edwina A Mambou, Zoe Yang, Aimee W Kao

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neurochemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. Article
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

8 authors.

Molly HodulDepartment of Neurology, University of California, San Francisco, California, USA.
Courtney Lane-DonovanDepartment of Neurology, University of California, San Francisco, California, USA.
Emily S CheangDepartment of Neurology, University of California, San Francisco, California, USA.
Vienna GaoDepartment of Neurology, University of California, San Francisco, California, USA.
Paul J SampognaroDepartment of Neurology, University of California, San Francisco, California, USA.
Edwina A MambouDepartment of Neurology, University of California, San Francisco, California, USA.
Zoe YangDepartment of Neurology, University of California, San Francisco, California, USA.
Aimee W KaoDepartment of Neurology, University of California, San Francisco, California, USA.ORCID https://orcid.org/0000-0002-7686-7968

Funding

Tau Metabolism in FTD: From Gene Mutations to Molecular Chaperones and Lysosomal ProteasesU54NS123985 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KARCH, CELESTE MARIE · 2021 to 2025
$9.0M
NINDS Research Education Programs for Residents and Fellows in Neurology, Neurosurgery, Neuropathology, Neuroradiology and Emergency Medicine (R25)R25NS070680 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JOSEPHSON, SCOTT ANDREW · 2010 to 2023
$6.8M
Systematic profiling of lysosomes with age to improve proteostasis in Alzheimer'sR01AG057342 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAO, AIMEE · 2018 to 2022
$3.8M
Understanding the molecular functions of progranulin and granulin in FTLDR01NS095257 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAO, AIMEE · 2015 to 2019
$1.9M
Progranulin, Prosaposin and Lipid Biology in FTDRF1NS127414 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAO, AIMEE · 2022 to 2023
$1.6M
TDP43 Degradation by the Lysosomal Proteases in Amyotrophic Lateral SclerosisK08NS121519 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Paul Joseph Sampognaro · 2022 to 2026
$1.1M
Progranulin Prosaposin and Lipid Biology in FTDR01NS127414 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Aimee Kao · 2025 to 2026
$922k
Illuminating Lysosomal Dysfunction in Aging and Alzheimer's Disease (AD)K08AG083050 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Courtney E Lane-Donovan · 2023 to 2026
$712k
Creative Minds CareJohn Douglas French Alzheimer's FoundationNIA NIH HHS K08 AG083050NIA NIH HHS K08AG083050NIA NIH HHS R01AG057342NINDS NIH HHS K08 NS121519NINDS NIH HHS R01NS095257NINDS NIH HHS R01 NS127414NINDS NIH HHS R25NS070680NINDS NIH HHS RF1NS127414NINDS NIH HHS U54NS123985Paul G. Allen Family FoundationRainwater Charitable FoundationWeill Institute for Neurosciences, University of California, San Francisco
6 · The paper itself

Abstract

Prosaposin (PSAP) is a lysosomal protein that plays a key role in sphingolipid metabolism. PSAP is cleaved into four bioactive disulfide-rich saposins (SapA, SapB, SapC, and SapD) that catalyze sphingolipidases to promote sphingolipid breakdown. Maintaining optimal levels of PSAP and saposins is crucial for proper lysosomal function and sphingolipid homeostasis, and PSAP dysfunction is associated with juvenile-onset lysosomal storage disorders and age-associated neurodegenerative disorders. Despite this, the mechanism by which saposins are released from PSAP, and thus available to modulate sphingolipidases, sphingolipid homeostasis, and downstream lysosomal function, is not well understood. Here, we performed a comprehensive study to identify lysosomal enzymes that regulated prosaposin cleavage into saposins. In vitro cleavage assays identified multiple enzymes that could process human prosaposin into multi- and single-saposin fragments. We confirmed the role of cathepsins D and B in PSAP processing and identified several additional lysosomal proteases (cathepsins E, K, L, S, V, G, and asparagine-specific endopeptidase) that were able to process PSAP in distinctive, pH-dependent manners. In addition, we found that PGRN and multi-granulin fragments (MGFs) directly regulated the cleavage of PSAP by cathepsin D. With this study, we have shown that multiple cathepsins, PGRN, and MGFs work in concert to produce saposins under different conditions, which could present novel opportunities to modulate saposin levels in disease.

Indexed as

CathepsinsIntercellular Signaling Peptides and ProteinsProgranulinsSaposinsAnimalsHumansLysosomesCathepsinsGRN protein, humanIntercellular Signaling Peptides and ProteinsProgranulinsPSAP protein, humanSaposinscathepsinslipid metabolismlysosomeprogranulinprosaposinproteolytic enzymesphingolipid

Identifiers

PMID41572567
PMCPMC12828107

What OpenQuestion holds

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LicenceCC BY-NC-ND
Read underepoch 390

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.