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Basic Science and Pathogenesis.

Jingyan Guo1, Linya You2, Yan Chen2

  • 1Tongji University, Shanghai, Shanghai, China.

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Summary
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This study introduces SpatialE, a tool for spatial transcriptomics analysis, revealing distinct brain region vulnerabilities for Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS) genes in the human cortex.

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Area of Science:

  • Neuroscience
  • Genomics
  • Computational Biology

Background:

  • The spatial organization of cell types and gene expression is crucial for brain function and disease, yet poorly understood in the human cortex.
  • Neurodegenerative diseases like Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS) show cell-type-specific vulnerabilities, but the regional susceptibility of associated genes remains unclear.

Purpose of the Study:

  • To develop and validate a computational tool, SpatialE, for identifying spatial gene set enrichment in spatial transcriptomics (ST) data.
  • To investigate the regional brain vulnerability of genes associated with AD and ALS in the human motor cortex and dorsolateral prefrontal cortex (DLPFC).

Main Methods:

  • Developed SpatialE, an entropy-weighted differential gene expression matrix-based tool for spatial enrichment analysis.
  • Benchmarked SpatialE against Multimodal Intersection Analysis (MIA) using human and mouse brain ST data.
  • Analyzed human motor cortex and DLPFC tissues using SpatialE and Cell2location for cell type deconvolution to assess AD and ALS gene enrichment and cell abundance.

Main Results:

  • SpatialE demonstrated superior accuracy and specificity in identifying spatial enrichment compared to MIA.
  • AD-associated genes were significantly enriched in Layer 1 (L1) of the human motor cortex, with abundant astrocytes identified in this layer.
  • ALS-associated genes were significantly enriched in Layer 5 (L5) of the motor cortex and DLPFC, with abundant upper motor neurons and L5 excitatory neurons found in L5 motor cortex.

Conclusions:

  • SpatialE is a novel computational tool for characterizing spatial gene expression patterns in ST data.
  • Spatial enrichment analysis revealed specific regional vulnerabilities in the human brain for AD and ALS-associated genes.