title: Analysis of RNA metabolism in peripheral WBCs of TDP-43 KI mice identifies novel biomarkers 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 43kDa (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 Naip5 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.
authors.affiliation: Division of Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 1058461, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Division of Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 1058461, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Hara-Miyauchi
authors.affiliation: Division of Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 1058461, Japan; Vascular Surgery, Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 1058461, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachidori Niigata Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Division of Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 1058461, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: hjokano@jikei.ac.jp.
authors.forename: Hirotaka James
authors.initials: HJ
authors.lastname: Okano
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000097:blood* / Q000175:diagnosis / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000097:blood / Q000235:genetics*; D055879:Gene Knock-In Techniques; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation; D012313:RNA / Q000378:metabolism*; D012333:RNA, Messenger / Q000097:blood
chemical_list: D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C000598624:TARDBP protein, human; D012313:RNA
keywords: ALS; Biomarker; Peripheral blood cells; RNA metabolism; TDP-43