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

Lauren M. Gittings, Eric B. Alsop, Jerry Antone, Mo Singer, Timothy G. Whitsett, Rita Sattler, Kendall Van Keuren-Jensen

Abstract

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.

Datasets

1. Frontal cortex samples from C9-ALS, C9-ALS/FTD and age matched control brains
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Preview
Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum
2. Occipital cortex samples from C9-ALS, C9-ALS/FTD and age matched control brains
Metadata
sample
chip
age_onset
age_death
duration
doublet_info
cluster
organism_ontology_term_id
tissue_ontology_term_id
assay_ontology_term_id
self_reported_ethnicity_ontology_term_id
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Preview
Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum
3. Frontal cortex samples from C9-FTD and age matched control brains
Metadata
sample
chip
age_onset
age_death
duration
doublet_info
cluster_layers
organism_ontology_term_id
tissue_ontology_term_id
assay_ontology_term_id
self_reported_ethnicity_ontology_term_id
development_stage_ontology_term_id
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S987620 cells
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Preview
Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum
4. Occipital cortex samples from C9-FTD and age matched control brains
Metadata
sample
chip
age_onset
age_death
duration
doublet_info
cluster
organism_ontology_term_id
tissue_ontology_term_id
assay_ontology_term_id
self_reported_ethnicity_ontology_term_id
development_stage_ontology_term_id
sex_ontology_term_id
donor_id
suspension_type
cell_type_ontology_term_id
disease_ontology_term_id
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
S1057567 cells
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S482788 cells
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S621976 cells
S61662 cells
Preview
Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum

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Source data

https://cellxgene.cziscience.com/collections/aee9c366-f2fb-470b-8937-577d5d87d3fc

Alias names

syn45351388, PMID37466726, PMC10412668

Cite this study

Gittings, L.M., Alsop, E.B., Antone, J., Singer, M., Whitsett, T.G., Sattler, R. and Van Keuren-Jensen, K., 2023. Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum. Acta neuropathologica, 146(3), pp.433-450. https://doi.org/10.1007/s00401-023-02599-5