Evidence map›Paper›PMID 33308480›Full record

ArticleDevelopmental cell2021

NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C.

Oliver B Davis, Hijai R Shin, Chun-Yan Lim, Emma Y Wu, Matthew Kukurugya, Claire F Maher, Rushika M Perera, M Paulina Ordonez, Roberto Zoncu

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

Article in Developmental cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 136 papers.

0numbers the graph read from it
0cells of the map it votes in
136citing papers in PubMed
12.4field-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

136 citing papers in PubMed, 191 citations in OpenAlex.

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  17. Noncanonical PI(4,5)PScience advances · 2026
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76 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors at 4 institutions in 1 country.

Oliver B DavisDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Hijai R ShinDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Chun-Yan LimDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Emma Y WuSanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California, San Diego, La Jolla, CA 92037, USA.
Matthew KukurugyaDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Claire F MaherDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Rushika M PereraDepartment of Anatomy and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
M Paulina OrdonezSanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: pordonez@health.ucsd.edu.
Roberto ZoncuDepartment of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: rzoncu@berkeley.edu.
University of California, Berkeley · USSanford Consortium for Regenerative Medicine · USUCSF Helen Diller Family Comprehensive Cancer Center · USUniversity of California, San Diego · US

Funding

Tracking tumor evolution through in vivo organelle profilingDP2CA216364 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PERERA, RUSHIKA MIRIAM · 2016 to 2016
$2.4M
Molecular mechanisms for lipid sensing by mTORC1R01GM127763 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI ZONCU, ROBERTO · 2019 to 2022
$1.4M
Spatio-temporal regulation of mTORC1 signaling in normal and disease statesR01GM130995 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI ZONCU, ROBERTO · 2019 to 2022
$1.2M
NCI NIH HHS DP2 CA216364NIGMS NIH HHS R01 GM127763NIGMS NIH HHS R01 GM130995
6 · The paper itself

Abstract

Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration. The compositional and functional alterations in NPC lysosomes and nature of aberrant cholesterol-mTORC1 signaling contribution to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion, enhanced membrane damage, and defective mitophagy. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.

Indexed as

HomeostasisSignal TransductionAdultAnimalsCells, CulturedCholesterolHEK293 CellsHumansInduced Pluripotent Stem CellsIntracellular MembranesIntracellular Signaling Peptides and ProteinsLysosomesMechanistic Target of Rapamycin Complex 1MiceMitochondriaModels, BiologicalCholesterolIntracellular Signaling Peptides and ProteinsMechanistic Target of Rapamycin Complex 1Niemann-Pick C1 ProteinNPC1 protein, humanNpc1 protein, mouseautophagycholesterolESCRTlysosomemitochondriamTORC1NPC1proteolysisproteomics

Identifiers

PMID33308480
PMCPMC8919971
OpenAlexW3111564394

What OpenQuestion holds

Textmetadata
LicenceTDM
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.