Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction
Year: 2026
Type: article
Abstract: TDP-43 pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report new TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7 and KCNQ2 . Using human stem cell-derived neurons, we show that TDP-43 reduction induces cryptic splicing and downregulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occur selectively in neurons with TDP-43 pathology. Importantly, suppressing individual cryptic splicing events using antisense oligonucleotides partially restores neuronal function, and combined targeting almost fully rescues the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.
Source: Science Translational Medicine
Authors: Caiwei Guo, Kuchuan Chen, Sarat Vatsavayai, Tetsuya Akiyama, Chang Liu, Yi Zeng, Odilia Sianto, Edith Yang, Juliane Bombosch, Rasheen Powell, Shannon Zhen, Shila Mekhoubad, Ryan D. Morrie, Georgiana Miller, Dragana Ilic, Moritz Boll, Euan Parnell, Peter Penzes, Noa Lipstein, Eric M. Green, Leonard Petrucelli, William W. Seeley, Aaron D. Gitler
Institutions: Stanford Medicine, Stanford University, Boston Children's Hospital, Harvard University, University of California, San Francisco, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Mayo Clinic, Northwestern University, University of Miami, Mayo Clinic in Florida, Chan Zuckerberg Biohub San Francisco
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Early Onset AD Consortium - the LEAD Study (LEADS), Early Onset Alzheimer's Disease Consortium, G9000150898, ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration, Cycle 2 (ALLFTD2), Defining modifiers and mechanisms of RAN translation, Frontotemporal Dementia: Genes, Images, and Emotions, Control of synaptic circuits by small GTPase pathways, Rac-GEF signaling in dendritic spines, Discovery of novel TDP-43 splicing targets: the Achilles heel for FTD and towards sensitive biomarkers and therapeutic targets, New Approaches to Dementia Heterogeneity, Innovating next generation technologies to define mechanisms of neurodegenerative disease and devise therapeutic strategies, New Approaches to Dementia Heterogeneity
OpenAlex ID: W4413916418