Modelling dementia in Drosophila uncovers shared and specific targets of TDP-43 proteinopathy across ALS and FTD relevant circuits

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 puncta that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous models of ALS, here we report a novel model of FTD based on overexpression of TDP-43 in the Drosophila mushroom body (MB) circuit. This model recapitulates several aspects of FTD pathology including age dependent neuronal loss, and nuclear depletion and cytoplasmic accumulation of TDP-43, accompanied by behavioral deficits in working memory and sleep that occur before axonal degeneration ensues. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit while others are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), a modulator of Wg/Wnt signaling. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits. These results highlight the utility of modelling TDP-43 proteinopathy in Drosophila and provide a novel platform for studying the molecular mechanisms underlying FTD, and potentially uncovering shared and circuit specific vulnerabilities in ALS/FTD.

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Work Title Modelling dementia in Drosophila uncovers shared and specific targets of TDP-43 proteinopathy across ALS and FTD relevant circuits
Subtitle Data summary files for Godfrey et al "Modelling dementia in Drosophila uncovers shared and specific targets of TDP-43 proteinopathy across ALS and FTD relevant circuits "
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Open Access
Creators
  1. Daniela Zarnescu
  2. R Keating Godfrey
License In Copyright (Rights Reserved)
Work Type Other
Publication Date April 4, 2023
DOI doi:10.26207/jq6p-w169
Deposited November 03, 2022

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Version 1
published

  • Created
  • Updated
  • Added Creator Daniela Zarnescu
  • Added Creator R Keating Godfrey
  • Updated Creator R Keating Godfrey
  • Updated Work Title, Description, Publication Date Show Changes
    Work Title
    • Keating Godfrey et al, A novel Drosophila model of FTD
    • Keating Godfrey et al, Drosophila models of TDP-43 proteinopathy uncover shared and specific mRNA targets across ALS and FTD relevant circuits
    Description
    • Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy. At the cellular level, TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 puncta that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous models of ALS, here we report a novel model of FTD based on overexpression of TDP-43 in the Drosophila mushroom body (MB) circuit. This model recapitulates several aspects of FTD pathology including age dependent nuclear depletion and cytoplasmic accumulation of TDP-43 accompanied by behavioral deficits in working memory and sleep that occur before axonal degeneration ensues. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are specific to the MB circuit and others that are shared with motor neurons. Using genetic interactions we show that overexpression of Dally-like-protein (Dlp), a modulator of Wg/Wnt signaling in MBs mitigates TDP-43 dependent working memory deficits. These results highlight the utility of modelling TDP-43 proteinopathy in Drosophila and provide a novel platform for studying the molecular mechanisms underlying FTD, and potentially uncovering circuit specific vulnerabilities in ALS/FTD.
    Publication Date
    • 11/7/2022
  • Updated Creator R Keating Godfrey
  • Added Figure_1D_RatioAnalysis.csv
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  • Updated Publication Date, License Show Changes
    Publication Date
    • 11/7/2022
    • 2022-11-07
    License
    • https://rightsstatements.org/page/InC/1.0/
  • Updated Work Title, Publication Date Show Changes
    Work Title
    • Keating Godfrey et al, Drosophila models of TDP-43 proteinopathy uncover shared and specific mRNA targets across ALS and FTD relevant circuits
    • Modelling dementia in Drosophila uncovers shared and specific targets of TDP-43 proteinopathy across ALS and FTD relevant circuits
    Publication Date
    • 2022-11-07
    • 2022-11-12
  • Updated Publication Date Show Changes
    Publication Date
    • 2022-11-12
    • 2022-11-14
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  • Updated Subtitle Show Changes
    Subtitle
    • Data summary files for Godfrey et al "Modelling dementia in Drosophila uncovers shared and specific targets of TDP-43 proteinopathy across ALS and FTD relevant circuits "
  • Published

Version 2
published

  • Created
  • Updated Description, Publication Date Show Changes
    Description
    • Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy. At the cellular level, TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 puncta that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous models of ALS, here we report a novel model of FTD based on overexpression of TDP-43 in the Drosophila mushroom body (MB) circuit. This model recapitulates several aspects of FTD pathology including age dependent nuclear depletion and cytoplasmic accumulation of TDP-43 accompanied by behavioral deficits in working memory and sleep that occur before axonal degeneration ensues. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are specific to the MB circuit and others that are shared with motor neurons. Using genetic interactions we show that overexpression of Dally-like-protein (Dlp), a modulator of Wg/Wnt signaling in MBs mitigates TDP-43 dependent working memory deficits. These results highlight the utility of modelling TDP-43 proteinopathy in Drosophila and provide a novel platform for studying the molecular mechanisms underlying FTD, and potentially uncovering circuit specific vulnerabilities in ALS/FTD.
    • Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy, which at the cellular level, is characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 puncta that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous models of ALS, here we report a novel model of FTD based on overexpression of TDP-43 in the Drosophila mushroom body (MB) circuit. This model recapitulates several aspects of FTD pathology including age dependent neuronal loss, and nuclear depletion and cytoplasmic accumulation of TDP-43, accompanied by behavioral deficits in working memory and sleep that occur before axonal degeneration ensues. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are unique to the MB circuit while others are shared with motor neurons. Among the latter is the glypican Dally-like-protein (Dlp), a modulator of Wg/Wnt signaling. Using genetic interactions we show that overexpression of Dlp in MBs mitigates TDP-43 dependent working memory deficits. These results highlight the utility of modelling TDP-43 proteinopathy in Drosophila and provide a novel platform for studying the molecular mechanisms underlying FTD, and potentially uncovering shared and circuit specific vulnerabilities in ALS/FTD.
    Publication Date
    • 2022-11-14
    • 2023-04-04
  • Updated Creator R Keating Godfrey
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