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Studies on activation of TFEB to promote autophagic degradation of alpha synuclein

Research Project

Project/Area Number 19K07843
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionShiga University of Medical Science

Principal Investigator

WALKER DOUGLAS  滋賀医科大学, 神経難病研究センター, 特任教授 (10813694)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Discontinued (Fiscal Year 2020)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsTFEB / alpha synuclein / Lewy body / autophagy / lysozome / tau / Parkinson's disease / Alzheimer's disease / polo-like kinase / transcription factor / phosphorylation
Outline of Research at the Start

The aim of this project is to demonstrate that enhancement of autophagy/lysosomal function through activation of Transcription Factor EB (TFEB) will increase the degradation of forms of alpha synuclein , particularly phosphorylated alpha synuclein, before it becomes deposited into Lewy bodies.

Outline of Annual Research Achievements

The aim of this project is to demonstrate that enhancement of autophagy/lysosomal
function through activation of Transcription Factor EB (TFEB) will increase the degradation of intracellular forms of disease-related proteins such as phosphorylated alpha synuclein (p-syn) and tau (p-tau). We examined the expression of progranulin (PGRN) and prosaposin (PSAP), regulators of lysosomal function, in the brain of Alzheiemer's disease (AD), and found the association of PGRN and PSAP with amyloid plaques in non-demented aged control and AD brains. Next, we investigated the possible involvement of PGRN and PSAP in tangle formation using human brain tissue sections of non-demented aged control subjects and AD cases, and compared with cases of fronto-temporal dementia (FTD) with granulin (GRN) mutations. The study revealed that decreased amounts of PGRN and PSAP proteins were detected in immature neurofibrillary tangles, while colocalization was still evident in adjacent neurons in all cases. Results suggest that neuronal loss of PGRN preceded loss of PSAP as tangles matured.The granulin mutation cases exhibited absence of PGRN in most neurons, while PSAP signal was preserved. We conclude that reduced levels of PGRN and PSAP and their interaction in neurons might predispose to accumulation of p-tau protein due to deficits in lysosomal activity.

Report

(2 results)
  • 2020 Annual Research Report
  • 2019 Research-status Report
  • Research Products

    (8 results)

All 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Int'l Joint Research] Banner Sun Health Institute/Arizona State University(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Effects of FTMT Expression by Retinal Pigment Epithelial Cells on Features of Angiogenesis2020

    • Author(s)
      Buyandelger Undral、Walker Douglas G.、Yanagisawa Daijiro、Morimura Toshifumi、Tooyama Ikuo
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 10 Pages: 3635-3635

    • DOI

      10.3390/ijms21103635

    • NAID

      120006862374

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel fluorinated derivative of curcumin negatively regulates thioredoxin-interacting protein expression in retinal pigment epithelial and macrophage cells2020

    • Author(s)
      Buyandelger Undral、Walker Douglas Gordon、Taguchi Hiroyasu、Yanagisawa Daijiro、Tooyama Ikuo
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 532 Issue: 4 Pages: 668-674

    • DOI

      10.1016/j.bbrc.2020.08.114

    • NAID

      120006887065

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Thioredoxin-Interacting Protein (TXNIP) with Focus on Brain and Neurodegenerative Diseases.2020

    • Author(s)
      Tsubaki H, Tooyama I, Walker DG
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 24 Pages: 9357-9357

    • DOI

      10.3390/ijms21249357

    • NAID

      120006951355

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains2020

    • Author(s)
      Walker Douglas G.、Tang Tiffany M.、Mendsaikhan Anarmaa、Tooyama Ikuo、Serrano Geidy E.、Sue Lucia I.、Beach Thomas G.、Lue Lih-Fen
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 2 Pages: 678-678

    • DOI

      10.3390/ijms21020678

    • Related Report
      2019 Research-status Report
  • [Journal Article] Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology2019

    • Author(s)
      Mendsaikhan Anarmaa、Tooyama Ikuo、Bellier Jean-Pierre、Serrano Geidy E.、Sue Lucia I.、Lue Lih-Fen、Beach Thomas G.、Walker Douglas G.
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 7 Issue: 1 Pages: 215-215

    • DOI

      10.1186/s40478-019-0862-8

    • NAID

      120006777342

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Microglial Phenotyping in Neurodegenerative Disease Brains: Identification of Reactive Microglia with an Antibody to Variant of CD105/Endoglin2019

    • Author(s)
      Walker Douglas、Lue Lih-Fen、Beach Thomas、Tooyama Ikuo
    • Journal Title

      Cells

      Volume: 8 Issue: 7 Pages: 766-766

    • DOI

      10.3390/cells8070766

    • Related Report
      2019 Research-status Report
  • [Presentation] mmunophenotyping of Microglia: Identification of a variant of CD105 as a marker of activated microglia in Alzheimer’s disease and Aged Brains2019

    • Author(s)
      D.G. Walker, L-F. Lue, T.G. Beach, I Tooyama
    • Organizer
      Alzheimer's Association International Conference 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2021-12-27  

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