TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Author:

Brown Anna-Leigh,Wilkins Oscar G.,Keuss Matthew J.,Hill Sarah E.ORCID,Zanovello Matteo,Lee Weaverly Colleen,Bampton Alexander,Lee Flora C. Y.,Masino Laura,Qi Yue A.,Bryce-Smith Sam,Gatt Ariana,Hallegger Martina,Fagegaltier Delphine,Phatnani Hemali,Phatnani Hemali,Kwan Justin,Sareen Dhruv,Broach James R.,Simmons Zachary,Arcila-Londono Ximena,Lee Edward B.,Van Deerlin Vivianna M.,Shneider Neil A.,Fraenkel Ernest,Ostrow Lyle W.,Baas Frank,Zaitlen Noah,Berry James D.,Malaspina Andrea,Fratta Pietro,Cox Gregory A.,Thompson Leslie M.,Finkbeiner Steve,Dardiotis Efthimios,Miller Timothy M.,Chandran Siddharthan,Pal Suvankar,Hornstein Eran,MacGowan Daniel J.,Heiman-Patterson Terry,Hammell Molly G.,Patsopoulos Nikolaos. A.,Butovsky Oleg,Dubnau Joshua,Nath Avindra,Bowser Robert,Harms Matthew,Aronica Eleonora,Poss Mary,Phillips-Cremins Jennifer,Crary John,Atassi Nazem,Lange Dale J.,Adams Darius J.,Stefanis Leonidas,Gotkine Marc,Baloh Robert H.,Babu Suma,Raj Towfique,Paganoni Sabrina,Shalem Ophir,Smith Colin,Zhang Bin,Harris Brent,Broce Iris,Drory Vivian,Ravits John,McMillan Corey,Menon Vilas,Wu Lani,Altschuler Steven,Lerner Yossef,Sattler Rita,Van Keuren-Jensen Kendall,Rozenblatt-Rosen Orit,Lindblad-Toh Kerstin,Nicholson Katharine,Gregersen Peter,Lee Jeong-Ho,Kokos Sulev,Muljo Stephen,Newcombe JiaORCID,Gustavsson Emil K.,Seddighi Sahba,Reyes Joel F.,Coon Steven L.,Ramos Daniel,Schiavo GiampietroORCID,Fisher Elizabeth M. C.,Raj TowfiqueORCID,Secrier MariaORCID,Lashley Tammaryn,Ule JernejORCID,Buratti EmanueleORCID,Humphrey Jack,Ward Michael E.,Fratta PietroORCID,

Abstract

AbstractVariants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1–3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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