Analysis of RNA metabolism in peripheral WBCs of TDP-43 KI mice identifies novel biomarkers of ALS. (May 2016)

• Record Type: Journal Article
• Authors: Hasegawa, Minami; Hara-Miyauchi, Chikako; Ohta, Hiroki; Sakimura, Kenji; Okano, Hideyuki; Okano, Hirotaka James
• Is Part Of: Neuroscience research. Volume 106(2016:May)
• Page Start: 12
• Page End: 22
• Publication Date: 2016-05
• Subjects: ALS -- Biomarker -- TDP-43 -- RNA metabolism -- Peripheral blood cells; Neurosciences -- Research -- Periodicals; Neurosciences -- Research -- Japan -- Periodicals; Neurology -- Periodicals; Neurosciences -- Periodicals; Neurosciences -- Recherche -- Périodiques; Neurosciences -- Recherche -- Japon -- Périodiques; Neurosciences -- Research; Japan; Periodicals; 612.8
• DOI: 10.1016/j.neures.2015.11.009
• Languages: English
• ISSNs: 0168-0102

Abstract

Highlights: To identify the biomarker of ALS, two kinds of mutant TDP-43 KI mice were used. Metabolisms of TDP-43 were changed in astrocytes and WBCs of mutant TDP-43 KI mice. Combination of survival and apoptosis-related factors may become a biomarker of ALS. Abstract: Diagnostic biomarkers for amyotrophic lateral sclerosis (ALS) have yet to be identified. One of the causes of neuronal cell death in neurodegenerative diseases is abnormal RNA metabolism, although the mechanisms by which this occurs are unclear. Detection of abnormal RNA metabolism in white blood cells (WBCs) could lead to a new biomarker of ALS onset. TAR DNA-binding protein 43 kDa (TDP-43) is an RNA-binding protein that regulates RNA metabolism. We previously developed a mouse model of ALS that exhibits adult-onset motor dysfunction; these mutant TDP-43 knock in (KI) mice heterozygously express mutant human TDP-43 (A382T or G348C). In the present study, we examined TDP-43 mRNA levels in WBCs of KI mice and found that A382T mutant mRNA is significantly higher than G348C. Our results suggest that each mutant TDP-43 induces distinct RNA metabolism, and that the expression of total TDP-43 alone in WBC is not suitable as an ALS biomarker. To identify additional candidates, we focused on survival and apoptosis-related factors and examined their mRNA metabolism in WBCs. mRNA levels of both Smn1 and Naip 5 correlated with TDP-43 levels and also differed between A382T and G348C. Together, TDP-43 and these factors may enable detection of abnormalities in individual ALS pathologies.