Multi-modal dissection of cell-type specific TDP-43 pathology in the motor cortex
Wolfgang P Ruf1,2, Julia K Kühlwein1, Laura Meier1
1Department of Neurology, University Clinic, University of Ulm, Ulm, Germany.
Abstract:
Cytoplasmic TDP-43 pathology is a pathological sign of ALS/ALS-FTD and a converging disease event across different genotypes, phenotypes and CNS areas. To understand this process and target it therapeutically, we need to define which cell types are affected and which cell-type specific effects make them particularly vulnerable. We coupled flow-cytometry nuclear sorting and sequencing with single-nucleus multi-omic ATAC-seq and RNA-seq and spatial transcriptomics to define the transcriptional cell type of affected neurons in the post-mortem ALS/ALS-FTD motor cortex (30 ALS, 20 ALS-FTD & 32 control samples). Here, we show that mainly excitatory cortical neurons are affected by TDP-43 pathology and define the cell types that are affected the most: intratelencephalic L2-L3-LINC00507-FREM3, L3-L5-RORB-LNX2, L3-L5-RORB-ADGRL4 & L6-THEMIS-LINC00343 neurons and extratelencephalic L5-FEZF2-NTNG1 neurons. Transcriptional aberrations by TDP-43 pathology, like cryptic exon inclusion, are cell-type specific and affect distinct gene sets in each cell type, highlighting the need to address TDP-43 pathology in a cell-type specific manner.
Insights
Cytoplasmic TDP-43 pathology primarily affects specific excitatory neurons in the brain, leading to cell-type specific transcriptional changes. Understanding these distinct effects is crucial for developing targeted therapies for ALS/ALS-FTD.
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.
