• Top page
  • Timetable
  • Per session
  • Per presentation
  • How to
  • Meeting Planner



Development of biomarkers in peripheral blood cells of ALS model mice

  • P1-310
  • 長谷川 実奈美 / Minami Hasegawa:1 原 央子 / Chikako Hara:1 岡野 ジェイムス洋尚 / Hirotaka James Okano:1 
  • 1:東京慈恵会医科大学 / Jikei University School of Medicine 

The diagnosis of ALS is still clinical and there is pronounced delay between onset of symptoms and diagnosis. Candidate drugs of ALS have been administrated to ALS patients before, but given little efficacy. It seems to be too late to treat the progressing disease when patients are diagnosed. TAR DNA binding protein 43 (TDP-43), an RNA binding protein, regulates a number of RNA splicing in nucleus, is found as a causative gene in both familial and sporadic ALS. TDP-43 has been considered the major pathological protein in ALS due to its formation of ubiquitin positive inclusion body and mislocalization in the cytoplasm of motor neurons of ALS patients (Arai et al. 2006). Interestingly, the cytoplasmic accumulation of TDP-43 has been shown to occur in circulating lymphomonocytes of ALS patients (Marco et al. 2011). If we detect abnormal TDP-43 dynamics directly or indirectly in symptomatic peripheral lymphomonocytes, it may enable early stage diagnosis of ALS that following early therapeutic intervention. In this study, we addressed whether changes of alternative splicing regulated by mutant TDP-43 in peripheral blood can work as a functional biomarker of ALS. To identify the candidates of biomarker, we performed the Alternative Splicing Microarray that globally detects changes of alternative splicing and gene expression in mutant TDP-43 from mutant TDP-43 KI mouse WBC on symptomatic stage. Genes more than 3 fold changes compared to WT were considered as a candidate of biomarker in ALS. We found the candidates included several factors associated with neuronal cell death. Thus, we investigated the changes in the levels of splice variants of these genes by RT-PCR. Some genes exhibited altered ratio of splice variants compared to WT. Our study indicates that mutant TDP-43 dysregulates the alternative splicing of target RNAs, thurefore the expression of abnormal transcripts may become a biomarker of ALS onset. In addition, to reveal whether the splice variant is associated with neurodegeneration, we evaluated the motor neuron cell death by over expressing of the splice variant in vitro.

Copyright © Neuroscience2014. All Right Reserved.