Clarification of pathophysiological role of astrocites that express transglutaminase 1 in prion diseases

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16904
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Hokkaido University
• Principal Investigator: Yamasaki Takeshi 北海道大学, 遺伝子病制御研究所, 客員研究員 (70709881)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 神経変性疾患 / Transglutaminase 1 / アストロサイト / プリオン病

Outline of Final Research Achievements

Alteration of the brain environment by activated glial cells is considered to be closely associated with the mechanism of neurodegeneration in many neurodegenerative diseases. However, the pathophysiological role of astrocytes in prion-diseases has not been fully understood. Previously, we analyzed the pathogenesis in prion-disease model mice, and found that the expression of Transglutaminase 1 (TGM1) was induced in astrocytes at the brain regions where neuronal loss was observed. Here, we analyzed relationship between the TGM1 expression and neurodegeneration using the co-culture system of prion-infected primary neurons and astrocytes. The imaging by super-resolution microscopy revealed the close association between TGM1 molecules and pathogenic prion proteins. However, we could not observe any cytotoxic effect by the TGM1 expression. Therefore, we developed a novel adeno-associated viral vector which enables the analysis of the function of TGM1-positive astrocytes.

Free Research Field

プリオン病学

Academic Significance and Societal Importance of the Research Achievements

プリオン病モデルマウスの脳内神経脱落部位でアストロサイトにTGM1が発現誘導されること、アストロサイトでのTGM1の発現がプリオン感染神経細胞に変性効果を示さないことを考えると、TGM1の直接的な神経変性への関与は薄いと考えられる。最近、TGM1が神経保護的なA2アストロサイトのマーカーとする報告が蓄積している一方で、アストロサイト亜集団をA1/A2の分類に留めず、神経変性疾患特異的なアストロサイト亜集団を考慮すべきという考え方も普及してきている。本研究で示されたウイルスベクターを用いた方法論は、TGM1陽性アストロサイトを含む疾患特異的なアストロサイト亜集団の機能解析への応用が期待できる。