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

Authors

Lauren M. Gittings, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.Follow
Eric B. Alsop, Neurogenomics Division, Translational Genomics Research Institute, part of City of Hope, Phoenix, AZ, USA.
Jerry Antone, Neurogenomics Division, Translational Genomics Research Institute, part of City of Hope, Phoenix, AZ, USA.
Mo Singer, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.
Timothy G. Whitsett, Neurogenomics Division, Translational Genomics Research Institute, part of City of Hope, Phoenix, AZ, USA.
Rita Sattler, Department of Translational Neuroscience, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA. Rita.sattler@barrowneuro.org.
Kendall Van Keuren-Jensen, Neurogenomics Division, Translational Genomics Research Institute, part of City of Hope, Phoenix, AZ, USA. kjensen@tgen.org.

Document Type

Article

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.

Keywords

Amyotrophic lateral sclerosis (ALS), C9ORF72, Cryptic exon (CE), Frontotemporal dementia (FTD), Single nuclei RNA sequencing, TAR DNA-binding protein 43 (TDP-43)

Medical Subject Headings

Humans; Amyotrophic Lateral Sclerosis (genetics, pathology); Frontotemporal Dementia (genetics, pathology); C9orf72 Protein (genetics, metabolism); Transcriptome; Pick Disease of the Brain (genetics); DNA-Binding Proteins (genetics, metabolism); Exons; Sequence Analysis, RNA

Publication Date

9-1-2023

Publication Title

Acta neuropathologica

E-ISSN

1432-0533

Volume

146

Issue

3

First Page

433

Last Page

450

PubMed ID

37466726

Digital Object Identifier (DOI)

10.1007/s00401-023-02599-5

Recommended Citation

Gittings, Lauren M.; Alsop, Eric B.; Antone, Jerry; Singer, Mo; Whitsett, Timothy G.; Sattler, Rita; and Van Keuren-Jensen, Kendall, "Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum" (2023). Translational Neuroscience. 2369.
https://scholar.barrowneuro.org/neurobiology/2369