Evaluation of PPAR-Delta/Gamma Agonist Therapy as a Novel Treatment Paradigm for ALS
[Technical Report, Annual Report]
CALIFORNIA UNIV IRVINE
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The nuclear receptor PPAR-delta is a highly expressed transcription factor in neurons and non-neuronal cells, and is required for neural function. PPAR-delta turns on genes that promote mitochondrial function and favor energy production, and genes that help neurons get rid of misfolded proteins and damaged organelles. PPAR-delta and a related transcription factor, PPAR-gamma, reduce inflammation. Drug compounds that activate PPAR-delta, known as agonists, can boost the function of processes that decline as we age and contribute to the development of neurodegenerative diseases, such as ALS. Here we will test if the PPAR deltagamma agonist T3D-959 can prevent cellular and molecular abnormalities in ALS, and if T3D-959 can improve the quality of life of mice that recapitulate key features of ALS. In the first Aim, we will evaluate T3D-959 in cultures of neurons expressing ALS-causing disease proteins. In the second Aim, we will test if T3D-959 drug treatment of mice that develop ALS is an effective therapy by tracking disease progression in T3D-959-treated ALS mice and in vehicle placebo-treated ALS mice, comparing outcomes of the two different cohorts. We will employ two different mouse models of ALS, one featuring expression of a disease protein TDP-43 implicated in ALS, and another based upon expressing the disease mutation underlying C9orf72 ALS, a common form of familial ALS.
- Medicine and Medical Research