Neuronal vulnerability and multilineage diversity in multiple sclerosis.

Area of Science:

• Neuroscience
• Immunology
• Genomics

Background:

• Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by relapsing-remission, distinct lesion pathology in grey and white matter, and progressive neurodegeneration.
• Understanding cellular and molecular changes within MS lesions is crucial for elucidating disease mechanisms and identifying therapeutic targets.

Purpose of the Study:

• To investigate cell-type-specific transcriptomic alterations in multiple sclerosis lesions.
• To identify vulnerable neuronal populations and glial activation patterns in the central nervous system during MS.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) was employed to profile gene expression changes across various cell lineages within MS lesions.
• Multiplex in situ hybridization was used for validation of key findings.
• Functional assays in mouse and human cell cultures confirmed microglial phagocytosis of myelin transcripts.

Main Results:

• Selective vulnerability and loss of CUX2-expressing excitatory projection neurons in upper-cortical layers were observed, associated with upregulation of stress-response genes and long non-coding RNAs.
• Signatures of stressed oligodendrocytes, reactive astrocytes, and activated microglia were predominantly found at the lesion rims.
• snRNA-seq identified phagocytosing microglia/macrophages ingesting myelin transcripts, further validated by functional assays.

Conclusions:

• MS lesions exhibit lineage- and region-specific transcriptomic changes, with distinct cortical neuron damage and glial activation patterns.
• Cortical neuron vulnerability and glial responses contribute to the progression of multiple sclerosis lesions.