Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum

The C9ORF72 -linked diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the nuclear depletion and cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43). Recent studies have shown that the loss of TDP-43 function leads to the inclusion of cryp...

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Bibliographic Details
Published in:Acta neuropathologica 2023-09, Vol.146 (3), p.433-450
Main Authors: Gittings, Lauren M., Alsop, Eric B., Antone, Jerry, Singer, Mo, Whitsett, Timothy G., Sattler, Rita, Van Keuren-Jensen, Kendall
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Analysis
Cortex (frontal)
Dementia disorders
DNA-binding protein
Exons
Frontotemporal dementia
Gene expression
Genes
Medical research
Medicine
Medicine & Public Health
Medicine, Experimental
Neurons
Neurosciences
Occipital lobe
Original Paper
Pathology
Protein binding
RNA
RNA sequencing
snRNA
Transcriptomics
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Summary:The C9ORF72 -linked diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the nuclear depletion and cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43). Recent studies have shown that the loss of TDP-43 function leads to the inclusion of cryptic exons (CE) in several RNA transcript targets of TDP-43. Here, we show for the first time the detection of CEs in a single-nuclei RNA sequencing (snRNA-seq) dataset obtained from frontal and occipital cortices of C9ORF72 patients that phenotypically span the ALS-FTD disease spectrum. We assessed each cellular cluster for detection of recently described TDP-43-induced CEs. Transcripts containing CEs in the genes STMN2 and KALRN were detected in the frontal cortex of all C9ORF72 disease groups with the highest frequency in excitatory neurons in the C9ORF72 -FTD group. Within the excitatory neurons, the cluster with the highest proportion of cells containing a CE had transcriptomic similarities to von Economo neurons, which are known to be vulnerable to TDP-43 pathology and selectively lost in C9ORF72 -FTD. Differential gene expression and pathway analysis of CE-containing neurons revealed multiple dysregulated metabolic processes. Our findings reveal novel insights into the transcriptomic changes of neurons vulnerable to TDP-43 pathology.
ISSN:0001-6322
1432-0533
DOI:10.1007/s00401-023-02599-5