Evaluation of PPAR-Delta/Gamma Agonist Therapy as a Novel Treatment Paradigm for ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the rapid and progressive loss of motor neurons in both the brain and spinal cord with an incidence of ~1 in 50,000. In about 90% of cases, there is no family history or clear inheritance of ALS. Because of the lack of a family history, this type of ALS is known as sporadic ALS (SALS). The other 10% of ALS cases are due to a genetic defect, and often there is a family history, with a parent and/or grandparent affected with ALS. Because of the inherited nature of the disease, we call this familial ALS (FALS). While there are many possible risk factors for ALS, the most compelling risk factor is age, as the vast majority of ALS patients are middle-aged or elderly. Our research and the work of many other investigators has linked the process of aging to a decline in the health of neurons in the central nervous system (CNS). Neurons and other cells in the CNS are unique in many regards, as they require high levels of energy to sustain multiple cellular and molecular processes. For example, neurons are constantly sending signals down their long axons, and so must use energy to propagate action potentials and also to transport materials from their cell bodies to dendrites and axons, and then back again. Research has shown that the disease process in ALS involves dysfunction of mitochondria, which are the organelles that produce high-energy molecules. As neurons age, they are faced with a number of stresses, including reduced mitochondrial function, an inability to clear misfolded proteins and damaged organelles, and increased susceptibility to activating pathways of inflammation. We recently found that the nuclear receptor PPAR-delta is a highly expressed transcription factor in neurons and non-neuronal cells and is required for normal neural function. PPAR-delta turns on genes that promote mitochondrial function and so favor production of energy, as well as turns on genes that help neurons to get rid of misfolded proteins and damaged organelles. PPAR-delta and a related transcription factor, known as PPAR-gamma, also reduce activation of inflammatory pathways. Our previous research has shown that drug compounds that activate PPAR-delta, known as "agonists," can boost the function of these processes, which decline as we age and contribute to the development of neurodegenerative diseases, such as ALS. In this project, we propose to test if a drug compound that mostly activates PPAR-delta and mildly activates PPAR-gamma could be an effective therapy for ALS. As research has shown that multiple pathways of homeostasis fail in motor neurons sickened in ALS, we expect that the PPAR-delta/gamma agonist T3D-959 could be an effective treatment for patients with both SALS and most forms of FALS. T3D-959 is a promising drug compound to test for ALS, because it is already approved for use in humans and was shown to be safe in both rodents and human patients. Indeed, T3D-959 may have potential as a therapy for a related neurodegenerative disorder, known as Alzheimer s disease. While Alzheimer s disease may seem quite different from ALS, it actually shares a number of features with ALS, as we now know that some ALS patients develop dementia in addition to muscle weakness and motor neuron disease. In this project, we propose to test if T3D-959 can prevent cellular and molecular abnormalities known to occur in SALS and in the most common form of FALS, known as C9orf72 ALS, and if T3D-959 can improve the quality of life of mice that recapitulate key features of ALS observed in SALS and/or in C9orf72 ALS. The project will consist of two Aims. In the first Aim, we will evaluate T3D-959 in cultures of neurons that will express ALS-causing disease proteins involved in SALS and C9orf72 ALS. In the second Aim, we will test if T3D-959 drug treatment of mice that develop ALS is an effective therapy by tracking the progression of the disease in T
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010154
Entities
People
- Albert La Spada
Organizations
- United States Army
- University of California, Irvine