Erroneous genetic sequences identified for the first time in specific cells of ALS and frontotemporal dementia patients

Good news! Are we finally zeroing in on discovering the genetics behind some of the severe neurodegenerative diseases!

Perhaps, there is hope for the senile, demented, and corrupted 46th President (pardon my bad joke)!

"Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with mean survival of 2-5 years and 6-8 years, respectively. ...

In some cases, the same genetic mutations occur in both. One of those mutations is a repetitive expansion in the DNA of a gene called C9ORF72. ... One of the significant changes that happens in the majority of cases of ALS and around half of the cases of FTD, is when a protein called TAR DNA binding protein (TDP-43) clumps together and stops working correctly. When TDP-43 doesn’t function properly, it puts incorrect genetic instructions into the RNA, which are called “cryptic exons.”
Now, a team of scientists ... have detected these cryptic exons in specific brain cells from ALS and FTD patients carrying a mutation in the C9ORF72 gene. ..."

From the 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."

Erroneous genetic sequences identified for the first time in specific cells of ALS and frontotemporal dementia patients | AZBio Gene splicing defect known as “cryptic exons” detected using single-nuclei RNA sequencing

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

Fig. 1 Detection of STMN2 and KALRN cryptic exons in single-nuclei sequencing data from subjects with C9-ALS, C9-ALS-FTD, and C9-FTD.