Evidence map›Paper›PMID 39223664›Full record

ArticleJournal of translational medicine2024

Tilorone mitigates the propagation of α-synucleinopathy in a midbrain-like organoid model.

Qi Zhang, Meng Liu, Yue Xu, Juhyung Lee, Brothely Jones, Bing Li, Wenwei Huang, Yihong Ye, Wei Zheng

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of translational medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed, 1 pooled it
–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

4 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Review
  3. Review
  4. 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

9 authors.

Qi ZhangTherapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20850, USA.
Meng LiuCancer Data Science laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Yue XuLaboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Juhyung LeeLaboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Brothely JonesTherapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20850, USA.
Bing LiTherapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20850, USA.
Wenwei HuangTherapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20850, USA.
Yihong YeLaboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. yihongy@mail.nih.gov.
Wei ZhengTherapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20850, USA. wzheng@mail.nih.gov.

Funding

Drug Repurposing Screening for Rare and Neglected DiseasesZIATR000018 · NCATS · NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES · PI ZHENG, WEI · 2015 to 2025
$24.6M
6 · The paper itself

Abstract

backgroundParkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons and the accumulation of Lewy-body protein aggregates containing misfolded α-synuclein (α-syn) in a phosphorylated form. The lack of effective models for drug screens has hindered drug development studies for PD. However, the recent development of in vitro brain-like organoids provides a new opportunity for evaluating therapeutic agents to slow the progression of this chronic disease.

methodsIn this study, we used a 3D brain-like organoid model to investigate the potential of repurposing Tilorone, an anti-viral drug, for impeding the propagation of α-synucleinopathy. We assessed the effect of Tilorone on the uptake of fluorescently labeled α-syn preformed fibrils (sPFF) and sPFF-induced apoptosis using confocal microscopy. We also examined Tilorone's impact on the phosphorylation of endogenous α-syn induced by pathogenic sPFF by immunoblotting midbrain-like organoid extracts. Additionally, quantitative RT-PCR and proteomic profiling of sPFF-treated organoids were conducted to evaluate the global impact of Tilorone treatment on tissue homeostasis in the 3D organoid model.

resultsTilorone inhibits the uptake of sPFF in both mouse primary neurons and human midbrain-like organoids. Tilorone also reduces the phosphorylation of endogenous α-syn induced by pathogenic α-syn fibrils and mitigates α-syn fibril-induced apoptosis in midbrain-like organoids. Proteomic profiling of fibril-treated organoids reveals substantial alterations in lipid homeostasis by α-syn fibrils, which are reversed by Tilorone treatment. Given its safety profile in clinics, Tilorone may be further developed as a therapeutic intervention to alleviate the propagation of synucleinopathy in PD patients.

Indexed as

alpha-SynucleinMesencephalonOrganoidsSynucleinopathiesAnimalsApoptosisHumansMiceModels, BiologicalParkinson DiseasePhosphorylationProteomicsalpha-SynucleinDrug preclinical developmentMidbrain-like organoidParkinson’s diseaseTiloroneα-synuclein

Identifiers

PMID39223664
PMCPMC11370279

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.