Nuclear depletion of RNA-binding protein ELAVL3 (HuC) in sporadic and familial amyotrophic lateral sclerosis.

Autor: Diaz-Garcia S; Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093-0670, USA., Ko VI; Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093-0670, USA., Vazquez-Sanchez S; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093-0670, USA.; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA., Chia R; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892-3707, USA., Arogundade OA; Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093-0670, USA., Rodriguez MJ; Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093-0670, USA., Traynor BJ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892-3707, USA., Cleveland D; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093-0670, USA.; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA., Ravits J; Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093-0670, USA. jravits@ucsd.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2021 Dec; Vol. 142 (6), pp. 985-1001. Date of Electronic Publication: 2021 Oct 07.
DOI: 10.1007/s00401-021-02374-4
Abstrakt: Amyotrophic lateral sclerosis is a progressive fatal neurodegenerative disease caused by loss of motor neurons and characterized neuropathologically in almost all cases by nuclear depletion and cytoplasmic aggregation of TDP-43, a nuclear RNA-binding protein (RBP). We identified ELAVL3 as one of the most downregulated genes in our transcriptome profiles of laser captured microdissection of motor neurons from sporadic ALS nervous systems and the most dysregulated of all RBPs. Neuropathological characterizations showed ELAVL3 nuclear depletion in a great percentage of remnant motor neurons, sometimes accompanied by cytoplasmic accumulations. These abnormalities were common in sporadic cases with and without intermediate expansions in ATXN2 and familial cases carrying mutations in C9orf72 and SOD1. Depletion of ELAVL3 occurred at both the RNA and protein levels and a short protein isoform was identified, but it is not related to a TDP-43-dependent cryptic exon in intron 3. Strikingly, ELAVL3 abnormalities were more frequent than TDP-43 abnormalities and occurred in motor neurons still with normal nuclear TDP-43 present, but all neurons with abnormal TDP-43 also had abnormal ELAVL3. In a neuron-like cell culture model using SH-SY5Y cells, ELAVL3 mislocalization occurred weeks before TDP-43 abnormalities were seen. We interrogated genetic databases, but did not identify association of ELAVL3 genetic structure with ALS. Taken together, these findings suggest that ELAVL3 is an important RBP in ALS pathogenesis acquired early and the neuropathological data suggest that it is involved by loss of function rather than cytoplasmic toxicity.
(© 2021. The Author(s).)
Databáze: MEDLINE
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