Establishment of RNA-based Biomarkers for ALS

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09766
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Okano Hirotaka James 東京慈恵会医科大学, 医学部, 教授 (90338020)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ALS / TDP-43 / 選択的スプライシング / RNA結合タンパク質

Outline of Final Research Achievements

We cloned and analyzed the promoter region of the TARDBP gene. TARDBP upstream sequences luciferase constructs were generated and their promoter activity was experimentally assessed. The upstream region predictably exhibited promoter activity and identified putative cis-acting elements, including the i-motif, was relevant for the regulation of TDP-43 expression. The cellular abundance of TDP-43 is strictly controlled, and its constancy is critically important for motor neuron survival. A machinery serving to maintain a constant level of TDP-43 is autoregulation via control of mRNA stability, a negative feedback system. We showed that TDP-43 negatively regulates the TARDBP promoter and, surprisingly, that disease-causing TDP-43 mutants lacked this regulatory activity. These results allowed the elucidation of a novel transcriptional autoregulatory mechanism of TDP-43 and quantification of the transcriptional activity could be a good biomarker to monitor the functional activity of TDP-43.

Free Research Field

分子神経科学

Academic Significance and Societal Importance of the Research Achievements

ALSは50～60代を中心とした成人の呼吸機能を含む運動機能を全廃に至らしめる最も悲惨な神経変性疾患の一つであるが、その発症原因はいまだ不明である。これまで多くの薬剤の臨床試験が行われてきたが、有効な治療薬の開発には至っていない。もしALSの発症早期に薬剤を投与し効果の判定ができれば、臨床試験で脱落した薬剤でさえ有効性が認められる可能性がある。しかし、ALSの早期診断を可能にするバイオマーカーが存在しないため早期治療介入は極めて難しい。優れたモデル動物が存在しない上、早期診断バイオマーカーが不在であることこそがALSの新規治療法開発を阻む原因であり、本計画で解決すべき課題であると考える。