Evidence map›Paper›PMID 40433888›Full record

ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025

Key Connectomes and Synaptic-Compartment-Specific Risk Genes Drive Pathological α-Synuclein Spreading.

Yuanxi Li, Justin Torok, Shujing Zhang, Jessica Ding, Ning Wang, Courtney Lau, Shruti Kulkarni, Chaitali Anand, Julie Tran, Michael Cheng and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. Article
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

17 authors.

Yuanxi LiDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.ORCID https://orcid.org/0000-0002-9170-7022
Justin TorokDepartment of Radiology, University of California, San Francisco, San Francisco, CA, 94117, USA.
Shujing ZhangDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Jessica DingDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Ning WangDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Courtney LauDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Shruti KulkarniDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Chaitali AnandDepartment of Radiology, University of California, San Francisco, San Francisco, CA, 94117, USA.
Julie TranDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Michael ChengDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Claire LoDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Binbin LuSmith College, Northampton, MA, 01063, USA.
Yanzi SunDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Robert DamoiseauxMolecular Screening Shared Resource (MSSR), California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.
Xia YangDepartment of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Ashish RajDepartment of Radiology, University of California, San Francisco, San Francisco, CA, 94117, USA.
Chao PengDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.ORCID https://orcid.org/0000-0002-1994-2087

Funding

UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's DiseaseR01AG072753 · NIA · WEILL MEDICAL COLL OF CORNELL UNIV · PI BUTLER, TRACY A., GUPTA, AJAY · 2021 to 2025
$5.3M
Regulation of Pathological Tau Transmission by Soluble Tau Post-Translational ModificationsR01NS128964 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Chao Peng · 2022 to 2026
$3.4M
Network Modelling of Multimodal Dynamics in Alzheimer’s Disease and DementiaRF1AG062196 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI NAGARAJAN, SRIKANTAN S., RAJ, ASHISH · 2019 to 2019
$3.0M
Precision Medicine Approach: Using genomic information to guide TBI treatmentR01NS111378 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI GOMEZ-PINILLA, FERNANDO, YANG, XIA · 2020 to 2024
$2.9M
Spatiotemporal Molecular Substrates of TBI at Single Cell ResolutionR01NS117148 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI GOMEZ-PINILLA, FERNANDO, WOLLMAN, ROY · 2020 to 2024
$2.8M
Mathematical modeling of selective vulnerability of genes, cells and network in mouse tauopathyRF1AG087302 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI RAJ, ASHISH · 2024 to 2024
$2.1M
Exploring the differential spreading of distinct pathological conformers of AD/LBD-related proteins by combining mathematical modeling and functional studyR21AG087921 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PENG, CHAO, RAJ, ASHISH · 2024 to 2025
$441k
Elman Family FundMichael J. Fox Foundation MJFF-009049Michael J. Fox Foundation MJFF-023428Michael J. Fox Foundation MJFF-024074NCATS NIH HHS UL1 TR001881NIA NIH HHS R01 AG072753NIA NIH HHS R21 AG087921NIA NIH HHS RF1 AG062196NIA NIH HHS RF1 AG087302NIH HHS R01-NS128964NIH HHS R21AG087921NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI UL1TR001881NIH/NIA RF1AG062196NIH/NIA RF1AG072753NIH/NINDS R01-NS111378NIH/NINDS R01-NS117148NINDS NIH HHS R01 NS111378NINDS NIH HHS R01 NS117148NINDS NIH HHS R01 NS128964Noble Family Innovation Fund
6 · The paper itself

Abstract

Previous studies have suggested that pathological α-synuclein (α-Syn) mainly transmits along the neuronal network, but several key questions remain unanswered: 1) How many and which connections in the connectome are necessary for predicting the progression of pathological α-Syn? 2) How to identify risk genes that affect pathology spreading functioning at presynaptic or postsynaptic regions, and are these genes enriched in different cell types? Here, these questions are addressed with novel mathematical models. Strikingly, the spreading of pathological α-Syn is predominantly determined by the key subnetworks composed of only 2% of the strongest connections in the connectome. Genes associated with the selective vulnerability of brain regions to pathological α-Syn transmission are further analyzed to distinguish those functioning at presynaptic versus postsynaptic regions. Those risk genes are significantly enriched in microglial cells of presynaptic regions and neurons of postsynaptic regions. Gene regulatory network analyses are then conducted to identify "key drivers" of genes responsible for selective vulnerability and overlapping with Parkinson's disease risk genes. By identifying and discriminating between key gene mediators of transmission operating at presynaptic and postsynaptic regions, this study has demonstrated for the first time that these are functionally distinct processes.

Indexed as

alpha-SynucleinConnectomeParkinson DiseaseSynapsesBrainGene Regulatory NetworksHumansNeuronsalpha-Synucleinkey connectomesmathematical modelspathological α‐synucleinrisk genessystems biology analyses

Identifiers

PMID40433888
PMCPMC12224943

What OpenQuestion holds

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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.