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Sans Nuclear TDP-43, Splicing of An ALS/FTD Gene Goes Awry

25 Apr 2021
In amyotrophic lateral sclerosis and frontotemporal dementia, loss of the RNA-binding protein TDP-43 from the nucleus creates a surge of mis-spliced mRNAs in neurons. So far, only one of these errant transcripts, stathmin-2, has been tied to disease pathology. Now, two preprints uploaded to bioRXiv on April 4 detail another UNC13A. Variants in this gene increase risk for ALS/FTD.
Neurons lacking nuclear TDP-43 mis-splice UNC13A, make less of the protein.
UNC13A risk variants incorporate cryptic exons.
This only occurs in brain and spinal cord tissue harboring TDP-43 deposits.
One paper was penned by researchers led by Pietro Fratta, University College London, and Michael Ward, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. The second is from the labs of Aaron Gitler, Stanford University, California, and Leonard Petrucelli, Mayo Clinic, Jacksonville, Florida. Both papers report that if TDP-43 binding to UNC13A falters, t ....

Johns Hopkins University , United States , New York , Stanford University , Baylor College Of Medicine , Matthew Keuss , Pietro Fratta , Rosa Ma , Mercedes Prudencio , Sarah Hill , Huda Zoghbi , Philip Wong , Aaron Gitler , Anna Leigh Brown , Yuka Koike , Oscar Wilkins , Leonard Petrucelli , Michael Ward , Chelsea Weidman Burke , University College London , York Genome Center , Mayo Clinic Brain Bank , National Institute Of Neurological Disorders , National Institute , Neurological Disorders , Mayo Clinic ,

Mayo Clinic Brain Bank - Mayo Clinic Research

Mayo Clinic Brain Bank
Mayo Clinic Brain Bank
Neuroscientists at Mayo Clinic s campus in Florida are leaders in the discovery of new genes, biomarkers and therapeutic targets for brain diseases. Thanks to exceptional resources, including a brain bank for neurodegenerative disorders housed within Dr. Dickson s Neuropathology and Microscopy Laboratory, Mayo investigators continue to shed new light on the underlying causes of Alzheimer s disease, Parkinson s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia and stroke.
Dennis W. Dickson, M.D., the Robert E. Jacoby Professor of Alzheimer s Research, is a member of the Department of Neuroscience. He is past president of the American Association of Neuropathologists and a Potamkin Prize winner. He directs the brain bank with the assistance of a dedicated staff of brain bank coordinators, neurohistology technical staff and professional support staff. The brain bank, which continues to grow, currently house ....

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