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; Claire Lo; Binbin Lu; Yanzi Sun; Robert Damoiseaux; Xia Yang; Ashish Raj; Chao Peng

doi:10.1002/advs.202413052

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

Adv Sci (Weinh). 2025 Jul;12(25):e2413052. doi: 10.1002/advs.202413052. Epub 2025 May 28.

Authors

Yuanxi Li^{1

2

3}, Justin Torok⁴, Shujing Zhang¹, Jessica Ding^{5

6}, Ning Wang⁵, Courtney Lau¹, Shruti Kulkarni¹, Chaitali Anand⁴, Julie Tran⁵, Michael Cheng⁵, Claire Lo¹, Binbin Lu⁷, Yanzi Sun¹, Robert Damoiseaux⁸, Xia Yang^{5

6

9

10

11}, Ashish Raj⁴, Chao Peng^{1

10

11

12}

Affiliations

¹ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
² Institute for Cognitive Neurodynamics, East China University of Science and Technology, Shanghai, 200237, China.
³ School of Mathematics, East China University of Science and Technology, Shanghai, 200237, China.
⁴ Department of Radiology, University of California, San Francisco, San Francisco, CA, 94117, USA.
⁵ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁶ Interdepartmental Program of Molecular, Cellular and Integrative Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁷ Smith College, Northampton, MA, 01063, USA.
⁸ Molecular Screening Shared Resource (MSSR), California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.
⁹ Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, 90095, USA.
¹⁰ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
¹¹ Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
¹² Mary S. Easton Center for Alzheimer's Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

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.

Keywords: key connectomes; mathematical models; pathological α‐synuclein; risk genes; systems biology analyses.

MeSH terms

Brain / metabolism
Brain / pathology
Connectome* / methods
Gene Regulatory Networks / genetics
Humans
Neurons / metabolism
Parkinson Disease* / genetics
Parkinson Disease* / metabolism
Parkinson Disease* / pathology
Synapses* / genetics
Synapses* / metabolism
alpha-Synuclein* / genetics
alpha-Synuclein* / metabolism

Substances

alpha-Synuclein

Abstract

MeSH terms

Substances

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