Elucidation of abnormal accumulation of DDX17 in motor neuron of ALS

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K14956
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Yokohama City University
• Principal Investigator: Tada Mikiko 横浜市立大学, 医学部, 助教 (30722467)
• Research Collaborator: Tanaka Fumiaki ; Doi Hiroshi ; Takeuchi Hideyuki ; Koyano Shigeru
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: ALS / DDX17 / RNA代謝異常 / SALS

Outline of Final Research Achievements

Growing evidences revealed that many common molecules exist in polyglutamine aggregate-interacting proteins (PAIPs) and pathological proteins of ALS. In this study, we focused on DDX17, which was previously identified as a PAIP (unpublished data). DDX17 is described as functioning in transcription, splicing and ribosomal RNA biogenesis. We hypothesized that DDX17 is implicated in pathomechanism of sporadic ALS (SALS). Therefore, we evaluated the subcellular distribution of DDX17 in SALS. As the result of immunohistochemistry using anti-DDX17 antibody, motor neuron of SALS cases showed diffuse immunoreactivity in cytoplasm and no immunoreactivity in nucleus as those in control cases. Additionally, small granules are also observed in the cytoplasm of motor neurons of SALS cases. Interestingly, these granules were co-localized with endoplasmic reticulum (ER) marker GRP78 or PDI. Our results indicated that DDX17 was accumulated in ER in SALS and were possibly involved in SALS pathogenesis.

Free Research Field

神経病理学

Academic Significance and Societal Importance of the Research Achievements

DDX17はRNA代謝においてリボソーマルRNA生成、スプライシング、転写といった重要なポイントに関与するとされている。一方ALSはその病因としてRNA代謝異常が注目されており、DDX17が孤発性ALSの病態に関連しているのではないかと仮説をたて研究を行った。検索を行ったALS全症例で脊髄前角細胞の細胞質に微細顆粒状の蓄積が観察された。またDDX17の細胞質への微細顆粒状蓄積は小胞体マーカーと共局在を確認できた。本研究の結果はDDX17が孤発性ALSの小胞体に蓄積することでALSの病態に関与している可能性を示し、ALSにおける神経細胞障害の新たな機序を解明するきっかけとなりうると考えられた。