Evidence map›Paper›PMID 40894642›Full record

ArticlebioRxiv : the preprint server for biology2025

Proteasome mutations associated with CANDLE syndrome cause altered neuronal development by dysregulating polyamine synthesis.

Clayton W Winkler, Benjamin Schwarz, Katie Williams, Sara Alehashemi, Simote T Foliaki, Joseph Snow, Lisa Joseph, Audrey Thurm, Christopher Friend, Gwendolyn Cooper and 13 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

23 authors.

Clayton W WinklerNeuroimmunology Section, Laboratory of Neurological Infections and Immunity (LNII), Rocky Mountain Laboratories (RML), National Institute of Allergy and Infectious Diseases (NIAID), NIH, Hamilton, MT, USA.
Benjamin SchwarzResearch and Technologies Branch, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Katie WilliamsPrion Cell Biology Unit, LNII, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Sara AlehashemiTranslational Autoinflammatory Diseases Section, Laboratory of Clinical Immunology & Microbiology (LCIM), NIAID, NIH, Bethesda, MD, USA.
Simote T FoliakiPrion Cell Biology Unit, LNII, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Joseph SnowNeuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health (NIMH), NIH, Bethesda, MD, USA.
Lisa JosephNeurodevelopmental and Behavioral Phenotyping Service, Intramural Research Program, NIMH, NIH, Bethesda, MD, USA.
Audrey ThurmNeurodevelopmental and Behavioral Phenotyping Service, Intramural Research Program, NIMH, NIH, Bethesda, MD, USA.
Christopher FriendTranslational Autoinflammatory Diseases Section, Laboratory of Clinical Immunology & Microbiology (LCIM), NIAID, NIH, Bethesda, MD, USA.
Gwendolyn CooperResearch and Technologies Branch, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Eric BohrnsenResearch and Technologies Branch, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Farzana BhuyanTranslational Autoinflammatory Diseases Section, Laboratory of Clinical Immunology & Microbiology (LCIM), NIAID, NIH, Bethesda, MD, USA.
Nathan T BrandesResearch and Technologies Branch, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Ruin MoaddelLaboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, MD USA.
Manfred BoehmLaboratory of Cardiovascular Regenerative Medicine, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Guibin ChenLaboratory of Cardiovascular Regenerative Medicine, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
Cole D KimzeyResearch and Technologies Branch, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Bibiana BielekovaNeuroimmunogical Diseases Section, LCIM, NIAID, NIH, Bethesda, MD, USA.ORCID 0000-0002-0959-9430
Joanna KocotNeuroimmunogical Diseases Section, LCIM, NIAID, NIH, Bethesda, MD, USA.
Peter KosaNeuroimmunogical Diseases Section, LCIM, NIAID, NIH, Bethesda, MD, USA.
Cathryn L HaighPrion Cell Biology Unit, LNII, RML, NIAID, NIH, Hamilton, MT 59840, USA.
Raphaela Goldbach-ManskyTranslational Autoinflammatory Diseases Section, Laboratory of Clinical Immunology & Microbiology (LCIM), NIAID, NIH, Bethesda, MD, USA.ORCID 0000-0003-4177-7249
Karin E PetersonNeuroimmunology Section, Laboratory of Neurological Infections and Immunity (LNII), Rocky Mountain Laboratories (RML), National Institute of Allergy and Infectious Diseases (NIAID), NIH, Hamilton, MT, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Genetic mutations affecting proteasome function can result in multi-organ diseases, such as Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. Neurological symptoms associated with CANDLE suggest that proteasomal mutations may impact neuronal development and/or function. We generated cerebral organoids (COs) from CANDLE patient induced pluripotent stem cells (iPSCs), which exhibited impaired neuronal development when compared to COs from healthy control iPSCs. Impaired neuronal maturation in CANDLE COs was correlated with increased polyamines, which were also elevated in CANDLE patient CSF. The proteasome-regulated Ornithine decarboxylase (ODC), a rate limiting enzyme for polyamines, was elevated in CANDLE neurons. Inhibition of ODC reversed polyamine overproduction and repaired neuronal maturation in CANDLE COs, suggesting a potential therapeutic avenue for intervention. These findings demonstrate that dysfunction of the proteasome affects neuronal development through overproduction of polyamines via dysregulation of ODC and offer insight into potential therapeutic strategies for CNS-related proteasomal dysfunction.

Identifiers

PMID40894642
PMCPMC12393280

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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.