PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43

Archi Joardar, Judith Menzl, Taylor C. Podolsky, Ernesto Manzo, Patricia S. Estes, Sarah Ashford, Daniela C Zarnescu

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. We have previously developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of disease pathophysiology. Using this model, we designed a drug screening strategy based on the pupal lethality phenotype induced by TDP-43 when expressed in motor neurons. In screening 1200 FDA-approved compounds, we identified the PPARγ agonist pioglitazone as neuroprotective in Drosophila. Here, we show that pioglitazone can rescue TDP-43-dependent locomotor dysfunction in motor neurons and glia but not in muscles. Testing additional models of ALS, we find that pioglitazone is also neuroprotective when FUS, but not SOD1, is expressed in motor neurons. Interestingly, survival analyses of TDP or FUS models show no increase in lifespan, which is consistent with recent clinical trials. Using a pharmacogenetic approach, we show that the predicted Drosophila PPARγ homologs, E75 and E78, are in vivo targets of pioglitazone. Finally, using a global metabolomic approach, we identify a set of metabolites that pioglitazone can restore in the context of TDP-43 expression in motor neurons. Taken together, our data provide evidence that modulating PPARγ activity, although not effective at improving lifespan, provides a molecular target for mitigating locomotor dysfunction in TDP-43 and FUS but not SOD1 models of ALS in Drosophila. Furthermore, our data also identify several 'biomarkers' of the disease that may be useful in developing therapeutics and in future clinical trials.

Original languageEnglish (US)
Article numberddu587
Pages (from-to)1741-1754
Number of pages14
JournalHuman Molecular Genetics
Volume24
Issue number6
DOIs
StatePublished - 2015

Fingerprint

pioglitazone
PPAR gamma
Amyotrophic Lateral Sclerosis
Drosophila
Motor Neurons
Peroxisome Proliferator-Activated Receptors
Clinical Trials
Neuromuscular Diseases
Preclinical Drug Evaluations
Metabolomics
Pharmacogenetics
Survival Analysis
Neuroglia
Biomarkers
Phenotype
Muscles

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Joardar, A., Menzl, J., Podolsky, T. C., Manzo, E., Estes, P. S., Ashford, S., & Zarnescu, D. C. (2015). PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. Human Molecular Genetics, 24(6), 1741-1754. [ddu587]. https://doi.org/10.1093/hmg/ddu587

PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. / Joardar, Archi; Menzl, Judith; Podolsky, Taylor C.; Manzo, Ernesto; Estes, Patricia S.; Ashford, Sarah; Zarnescu, Daniela C.

In: Human Molecular Genetics, Vol. 24, No. 6, ddu587, 2015, p. 1741-1754.

Research output: Contribution to journalArticle

Joardar, A, Menzl, J, Podolsky, TC, Manzo, E, Estes, PS, Ashford, S & Zarnescu, DC 2015, 'PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43', Human Molecular Genetics, vol. 24, no. 6, ddu587, pp. 1741-1754. https://doi.org/10.1093/hmg/ddu587
Joardar A, Menzl J, Podolsky TC, Manzo E, Estes PS, Ashford S et al. PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. Human Molecular Genetics. 2015;24(6):1741-1754. ddu587. https://doi.org/10.1093/hmg/ddu587
Joardar, Archi ; Menzl, Judith ; Podolsky, Taylor C. ; Manzo, Ernesto ; Estes, Patricia S. ; Ashford, Sarah ; Zarnescu, Daniela C. / PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 6. pp. 1741-1754.
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