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RNA regulation in neural development and diseases

開催日 2014/9/11
時間 14:00 - 16:00
会場 Room E(301)
Chairperson(s) 河原 行郎 / Yukio Kawahara (大阪大学大学院医学系研究科遺伝子機能制御学 / Osaka University, Graduate School of Medicine, Japan)
築地 仁美 / Hitomi Tsuiji (名古屋市立大学大学院薬学研究科 病態生化学分野 / Department of Biomedical Science, Nagoya City University, Graduate School Pharmaceutical Science, Japan)

Abnormal RNA metabolism in motor neuron disease ALS

  • S1-E-2-2
  • 築地 仁美 / Hitomi Tsuiji:1 
  • 1:名古屋市立大学・薬・病態生化 / Dept Biomedical Sci, Nagoya City Univ Grad Sch Pharmaceutical Science, Aichi, Japan 

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by rapidly progressive paralysis and death from respiratory failure, typically within 2 to 3 years of symptom onset. Considerable efforts have been made to identify causative genes underlying ALS, and as of yet, genes in ~70% of familial cases (in Europe) have been discovered. About 50% of familial cases carry mutations in genes coding RNA-binding proteins such as TARDBP and FUS, or have expansion of intronic hexanucleotides repeats that results in abnormal RNA aggregates, highlighting the importance of abnormal RNA metabolism in motor neuron degeneration. We have recently demonstrated that abnormal RNA metabolism in spinal motor neurons of ALS patients is similar to that in spinal motor neuron in spinal muscular atrophy (SMA), child motor neuron disease. Spliceosome components are abnormally accumulated in nucleus of affected neurons, indicating for the first time spliceosomal defects in ALS spinal motor neuron as implicated in SMA. I will discuss about newly identified ALS causative RNA-binding protein that abnormally accumulates in nucleus of ALS spinal motor neuron. On the other hands, taking into consideration TDP-43 protein (coded by TARDBP) being a major component of the ubiquitin-positive neuronal inclusion that are the pathological hallmark of both ALS and frontotemporal dementia (FTD), we had developed transgenic mice expressing human TDP-43 mainly in the central neuve system under prion promoter to model FTD-ALS. Although the TDP-43 transgenic mice did not display TDP-43 proteinopathy, did display impaired memory in fear conditioning test at 8-month old, indicating that the mice recapitulate some phenotype of FTD patients. The investigation of a region-specific effect of TDP-43 on mRNA expression and splicing in the mice revealed that the expression of several genes crucial for neuronal function, including a potassium channel binding protein, were down-regulated in the TDP-43 transgenic mice in a region-specific manner. Moreover, the expression level of a molecule that could enhance the production of reactive oxygen species was up-regulated. The changes in these genes might cause neuronal dysfunction in the TDP-43 transgenic mice.

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