Development of a Novel Treatment for Malignant Brain Tumors by Controlling Polyglutamylation

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K09485
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Kumamoto University
• Principal Investigator: Shinojima Naoki 熊本大学, 病院, 講師 (50648269)
• Co-Investigator(Kenkyū-buntansha): 市村 幸一 順天堂大学, 医学部, 特任教授 (40231146) ; 田崎 雅義 熊本大学, 大学院生命科学研究部(保), 准教授 (50613402) ; 武笠 晃丈 熊本大学, 大学院生命科学研究部(医), 教授 (90463869) ; 藤本 健二 熊本大学, 病院, 医員 (70844413) ; 大田 和貴 熊本大学, 医学部附属病院, 医員 (60794469)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: ポリグルタミル化 / 中枢神経原発悪性リンパ腫 / 脳腫瘍 / 認知機能

Outline of Final Research Achievements

With regard to the molecular mechanisms of polyglutamylation regulation in primary central nervous system lymphoma (PCNSL), we found that polyglutamylation is involved in epigenetics. In addition, we found that the polyglutamylation rate and phosphorylated Tau protein expression were correlated in PCNSL, and that cognitive function was significantly impaired in the group with high polyglutamylation in PCNSL patients. It is well known that PCNSL often develops with cognitive impairment. The involvement of polyglutamylation/Tau was suggested as one of the causes of cognitive impairment in PCNSL. With regard to new treatments, the antitumor effect was enhanced when methotrexate (MTX) was used in combination with HDAC inhibitors in vitro and in vivo to induce MTX polyglutamylation.

Free Research Field

脳腫瘍

Academic Significance and Societal Importance of the Research Achievements

ポリグルタミル化（PG化）の制御は、中枢神経原発悪性リンパ腫（PCNSL）のメソトレキセート治療効果を増強するだけでなく、アルツハイマー型認知症をはじめとするTau蓄積が関与する認知症治療にも効果が期待できる可能性が示唆された。PG化制御の機序解明はPCNSL治療だけでなく、超高齢社会にある日本で今後益々増加傾向にある認知症の新規治療開発にも繋がるpromisingな研究と考える。