![]() Another SNP- rs12608932 1 -is located 534 bp downstream of the donor splice site of the CE within the same intron (hereafter referred to as the intronic SNP) (Fig. One ALS-TDP and FTLD-TDP risk SNP- rs12973192 15-lies 16 bp inside the CE (hereafter referred to as the CE SNP). 1b), and increased intron retention between exons 31 and 32 (Extended Data Fig. Inspection of UNC13A splicing revealed the presence of a CE, occurring in two forms distinguishable by their size, between exons 20 and 21 after TDP-43 knockdown (Fig. UNC13A polymorphisms modify both disease risk and progression in ALS and FTLD-TDP 1, 2, 3, 15, 17, 18, 19, suggesting a potential functional relationship between TDP-43, UNC13A and disease risk. Of the 179 CE-harbouring genes, only the synaptic gene UNC13A was also an ALS–FTD risk gene (Fig. We examined splicing, expression, ALS GWAS 15 risk genes and diagnostic panel genes for ALS and FTD 16. Differential splicing and expression analyses identified 179 CEs, including several that have been reported previously, in genes including AGRN, RAP1GAP, PFKP and STMN2 7, 8, 14 (Fig. To identify novel CEs promoted by TDP-43 depletion, we performed RNA sequencing (RNA-seq) on human induced pluripotent stem (iPS) cell-derived cortical-like i 3Neurons, in which we reduced TDP-43 expression using CRISPR inhibition 11, 12, 13 (CRISPRi). Collectively, our findings reveal the molecular mechanism behind one of the top GWAS hits for ALS and FTD and provide a promising new therapeutic target for TDP-43 proteinopathies. Notably, intronic risk-associated single nucleotide polymorphisms (SNPs) for ALS and FTD in UNC13A promote increased inclusion of this CE. This CE promotes nonsense-mediated decay (NMD) and UNC13A transcript and protein loss. Here we report the presence of a CE in UNC13A, which is present at high levels in neurons from patients with ALS and FTLD-TDP. This STMN2 CE is selectively expressed in affected tissue, and its level correlates with TDP-43 phosphorylation, enabling it to serve as a functional readout for TDP-43 proteinopathy 8, 9, 10. However, a link between CEs and disease risk has not yet been established. One such CE occurs in the stathmin 2 ( STMN2) transcript 8, 9. These events are referred to as cryptic exons (CEs) and often lead to premature stop codons and transcript degradation, or premature polyadenylation 7. ![]() Upon loss of nuclear TDP-43-an early pathological feature in TDP-43-associated ALS (ALS-TDP) and FTLD-TDP-non-conserved intronic sequences are de-repressed and erroneously included in mature RNAs. TDP-43 is an RNA-binding protein (RBP) that resides primarily in the nucleus and has key regulatory roles in RNA metabolism, including as a splicing repressor. Genome-wide association studies (GWAS) have repeatedly demonstrated a shared risk locus for ALS and FTD in the crucial synaptic gene UNC13A, although the mechanism underlying this association has remained unknown 1, 2, 3.ĪLS and FTD are pathologically defined by cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) in more than 97% of ALS cases and 45% of FTD cases 4, 5 (frontotemporal lobar degeneration (FTLD) due to TDP-43 proteinopathy (FTLD-TDP)). Nature volume 603, pages 131–137 ( 2022) Cite this articleĪmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating adult-onset neurodegenerative disorders with shared genetic causes and common pathological aggregates 6. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |