Low molecular weight species of TDP-43 generated by abnormal splicing form inclusions in amyotrophic lateral sclerosis and result in motor neuron death

Acta Neuropathologica
Shangxi XiaoJanice Robertson

Abstract

The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-binding protein 43 (TDP-43) is a characteristic of TDP-43 proteinopathy in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we have identified a novel splice variant of TDP-43 that is upregulated in ALS and generates a 35-kDa N-terminally truncated species through use of an alternate translation initiation codon (ATG(Met85)), denoted here as Met(85)-TDP-35. Met(85)-TDP-35 expressed ectopically in human neuroblastoma cells exhibited reduced solubility, cytoplasmic distribution, and aggregation. Furthermore, Met(85)-TDP-35 sequestered full-length TDP-43 from the nucleus to form cytoplasmic aggregates. Expression of Met(85)-TDP-35 in primary motor neurons resulted in the formation of Met(85)-TDP-35-positive cytoplasmic aggregates and motor neuron death. A neo-epitope antibody specific for Met(85)-TDP-35 labeled the 35-kDa lower molecular weight species on immunoblots of urea-soluble extracts from ALS-FTLD disease-affected tissues and co-labeled TDP-43-positive inclusions in ALS spinal cord sections, confirming the physiological relevance of this species. These results show that the 35-kDa low molecular ...Continue Reading

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Citations

Nov 4, 2015·Brain : a Journal of Neurology·Laura MacNairJanice Robertson
Dec 18, 2015·Neuroscience Research·Minami HasegawaHirotaka James Okano
Jul 30, 2015·Neurobiology of Disease·Guinevere F LourencoGlenda M Halliday
Mar 24, 2016·Mechanisms of Ageing and Development·Bahareh EftekharzadehSusanne Wegmann
Jun 9, 2016·Acta Neuropathologica·Steven BoeynaemsLudo Van Den Bosch
Oct 4, 2016·Progress in Neurobiology·Erika N GuerreroMuralidhar L Hegde
Feb 28, 2018·Journal of Neurochemistry·Ju GaoXinglong Wang
Oct 3, 2018·Expert Review of Neurotherapeutics·Arens Taga, Nicholas J Maragakis
Nov 9, 2019·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·Anne GieselerKarl-Heinz Zacher
Sep 12, 2015·Current Opinion in Neurology·Pierre-François PradatClaude Desnuelle
Jul 4, 2019·Acta Neuropathologica Communications·Keith A JosephsDennis W Dickson
Oct 28, 2017·Frontiers in Microbiology·Renée N Douville, Avindra Nath
Jan 11, 2020·Frontiers in Molecular Neuroscience·Liberty François-MoutalMay Khanna
Nov 9, 2016·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Yulong Sun, Avi Chakrabartty
Apr 30, 2019·Frontiers in Neuroscience·Britt A Berning, Adam K Walker
Aug 18, 2020·Molecular Neurodegeneration·Terry R Suk, Maxime W C Rousseaux
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Feb 13, 2018·Expert Opinion on Therapeutic Targets·Emanuele Buratti
Jan 31, 2020·Frontiers in Molecular Biosciences·Suvithanandhini LoganathanDaniela C Zarnescu
Mar 28, 2021·Journal of Molecular Biology·Shailendra DhakalVijayaraghavan Rangachari
May 21, 2021·IScience·Deepak ChhanganiDiego E Rincon-Limas
Jan 24, 2017·Biochemistry·Yulong Sun, Avijit Chakrabartty
Jun 12, 2021·Brain : a Journal of Neurology·Hadjara SidibéChristine Vande Velde

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Datasets Mentioned

BETA
BI464234
BG435185

Methods Mentioned

BETA
PCR

Software Mentioned

ImageJ
Image J
Volocity
Volocity Imaging
Openlab Imaging

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