Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex.

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Cytoplasmic TDP-43 pathology is a hallmark of Amyotrophic Lateral Sclerosis (ALS) and ALS with Frontotemporal Dementia (ALS-FTD).
• Identifying affected cell types and their specific vulnerabilities is key to understanding disease mechanisms and developing targeted therapies.

Purpose of the Study:

• To define the transcriptional cell types of neurons affected by TDP-43 pathology in the motor cortex of ALS/ALS-FTD patients.
• To identify cell-type specific transcriptional aberrations caused by TDP-43 pathology.

Main Methods:

• Coupled flow-cytometry nuclear sorting and sequencing with single-nucleus multi-omic ATAC-seq and RNA-seq.
• Utilized spatial transcriptomics on post-mortem motor cortex samples from ALS/ALS-FTD patients and controls.

Main Results:

• Excitatory cortical neurons are predominantly affected by TDP-43 pathology.
• Specific neuronal subtypes, including intratelencephalic L2-L3-LINC00507-FREM3, L3-L5-RORB-LNX2, L3-L5-RORB-ADGRL4, L6-THEMIS-LINC00343, and extratelencephalic L5-FEZF2-NTNG1 neurons, are most impacted.
• TDP-43 pathology induces cell-type specific transcriptional changes, such as cryptic exon inclusion, affecting distinct gene sets.

Conclusions:

• TDP-43 pathology impacts specific subtypes of excitatory neurons in the ALS/ALS-FTD motor cortex.
• Transcriptional aberrations are cell-type specific, necessitating cell-type specific therapeutic strategies for TDP-43 related neurodegenerative diseases.