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Spatial transcriptomics links hippocampal synaptic remodeling to microglial phagocytosis in synucleinopathy
Min-Tae Jeon1, Jisu Jeong1, Moonseok Choi1
1Dementia Research Group, Korea Brain Research Institute, Daegu 41062, South Korea.
Journal of Advanced Research
|May 22, 2026
Summary
The G2-3 synucleinopathy mouse model shows significant hippocampal vulnerability, with altered synaptic function and MAPK signaling. Spatial transcriptomics reveals region-specific pathology, offering insights into synucleinopathies like Parkinson's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Synucleinopathies, including Parkinson's disease (PD) and Lewy body dementia (LBD), are characterized by alpha-synuclein (α-syn) aggregation.
- These neurodegenerative diseases exhibit region-specific vulnerability, but the mechanisms, especially in the hippocampus, are poorly understood.
Purpose of the Study:
- To investigate if the G2-3 α-synuclein transgenic mouse model replicates human synucleinopathy region-specific vulnerabilities.
- To identify molecular and cellular mechanisms driving region-specific pathology in this model.
Main Methods:
- Spatial transcriptomics profiling of G2-3 mice and wild-type littermates.
- Gene Ontology (GO) and KEGG pathway enrichment analyses.
- Validation using immunohistochemistry and cell-type deconvolution.
Main Results:
- The hippocampus, particularly DG and CA subfields, displayed the most significant transcriptomic alterations in G2-3 mice.
- Enrichment of synapse-related processes and MAPK signaling pathways was observed.
- Immunohistochemistry confirmed PSD95 mislocalization and increased neuronal p-ERK, indicating synaptic and molecular vulnerabilities.
Conclusions:
- The G2-3 mouse model exhibits selective hippocampal vulnerability with transcriptional and structural synaptic alterations.
- Spatial transcriptomics successfully identified key molecular pathways (MAPK signaling) and synaptic changes in the hippocampus.
- This study provides mechanistic insights into hippocampal vulnerability in synucleinopathies and validates spatial transcriptomics as a discovery tool.
