title: PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43.
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.
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Archi
authors.initials: A
authors.lastname: Joardar
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Judith
authors.initials: J
authors.lastname: Menzl
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Podolsky
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Manzo
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Estes
authors.affiliation: Department of Molecular and Cellular Biology.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ashford
authors.affiliation: Department of Molecular and Cellular Biology, Department of Neuroscience Department of Neurology, University of Arizona, Tucson, AZ 85721, USA zarnescu@email.arizona.edu.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Zarnescu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics; D004195:Disease Models, Animal; D004330:Drosophila / Q000187:drug effects / Q000235:genetics; D029721:Drosophila Proteins / Q000819:agonists / Q000235:genetics; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C083810:Eip78C protein, drosophila; C000599550:FUS protein, human; D018696:Neuroprotective Agents; D047495:PPAR gamma; D034702:RNA-Binding Protein FUS; D018160:Receptors, Cytoplasmic and Nuclear; C000589036:TBPH protein, Drosophila; D045162:Thiazolidinediones; D014157:Transcription Factors; C061375:Eip75B protein, Drosophila; D000077205:Pioglitazone