7月7日（金） 11:40-12:40 Room B
2JS③-1
C9orf72-FTD/ALSにおけるジペプチドリピートタンパク質の毒性メカニズムとその発現を抑制するための戦略
Possible mechanisms of dipeptide repeat protein toxicity and strategies to suppress their expression in C9orf72-FTD/ALS
森 康治
大阪大学大学院医学系研究科精神医学
Kohji Mori
Psychitary, Osaka University Graduate School of Medicine
Frontotemporal dementia (FTD) is characterized with behavioral disturbance and/or progressive aphasia with corresponding frontal and/or temporal lobar atrophy. An aberrant GGGGCC repeat expansion located in intron of C9orf72 (chromosome 9 open reading frame 72) gene is a leading genetic cause of familial forms of both FTD and amyotrophic lateral sclerosis (ALS). The expanded DNA repeat is bidirectionally transcribed into sense and antisense repeat RNA and they form RNA foci. Part of the repeat RNA transcripts are translated into dipeptide repeat protein (DPR) through repeat associated non-AUG (RAN) translation. DPR forms disease-characterizing inclusions in the brain of C9orf72-FTD/ALS patients. Since multilateral potential toxicities of DPR are demonstrated in multiple disease models, selective inhibition of RAN translation might have therapeutic potential. Here I would like to summarize the toxic mechanisms of DPR and discuss about the strategies to reduce their expression. | | 7月7日（金） 11:40-12:40 Room B
2JS③-2
トリプレットリピート病におけるRNA毒性
RNA toxicity in trinucleotide repeat expansion disorders
中森 雅之
山口大学 臨床神経学
Masayuki Nakamori
Dept. of Neurology, Yamaguchi Univ., Yamaguchi, Japan
Trinucleotide repeat expansion disorders (TREDs), such as Huntington's disease, spinocerebellar ataxias, and myotonic dystrophy, arise from the abnormal expansion of the trinucleotide repeat sequence. TREDs fall into two broad categories according to the position of the repeat element within the mutant gene. When an anomalous repetition is found within the protein translation domain, as seen in Huntington's disease, an atypical protein provokes neuronal impairment. The second major group of TRED is caused by repeats in non-protein-coding regions of genes. For these disorders, the genetic features and mechanisms are more diverse. In myotonic dystrophy type 1 (DM1), which ensues from an anomalous expansion of the CTG repeat in the 3' UTR of the DMPK gene, transcribed RNA harboring an excessively expanded CUG repeat disrupts the functioning of RNA binding proteins, including splicing factors. This disturbance in the regulation of alternative splicing engenders a multitude of symptoms in DM1. Consequently, in TREDs characterized by abnormally expanded repeats in the untranslated regions, the central mechanism of pathogenesis is attributed to the toxicity induced by abnormal RNA. |
