Developing UPR Modulators as Novel Therapeutics for Neurodegeneration

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal disease that kills motor neurons of the spinal cord, cerebral cortex and brainstem. Sporadic and familial ALS are indistinguishable in the clinicsuggesting common pathological mechanisms. Thus, the discovery that patients with familial ALS often harbor dominant gain-of-function toxic mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) is a major mechanistic clue. mutSOD1 misfolds andaggregates to form neuronal inclusion bodies. While their role is not fully defined, these aggregates appear before neuronal death in animal models and strongly correlate with disease progression. Furthermore, evidence suggests that these aggregates causeendoplasmic reticulum (ER) stress-induced neurotoxicity that plays a central role in disease pathology. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities and ER-associated protein degradation. If homeostasis is not restored through these outputs, the UPR triggers apoptosis. Our team recently discovered that a key component of the UPR, IRE1a, acts as a toggling switch between homeostaticand apoptotic outputs, ultimately controlling cell fate. The project goal of this STTR is to develop small molecules that bias IRE1a's outputs towards homeostasis and to demonstrate the therapeutic potential of these compounds in ALS. We have developed anovel biochemical assay to detect such compounds, and have identified good starting points for medicinal chemistry. A novel mutSOD1 embryonic stem cell-derived cell culture model of neurodegeneration designed to evaluate UPR mechanism-based neuroprotectionwill help us drive the functional potency of these compounds. Results from the proposed studies will guide our selection of lead compounds to validate this approach in the mutSOD1 ALS mouse model. Ultimately, these efforts represent a significant step towards the development of a novel treatment for ALS and related NDs. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disease (ND) that typically strikes between the ages of 40 and 70. The central pathological hallmark of ALS is the selective loss of motor neurons of the spinal cord, cerebral cortex and brainstem. These mounting losses destroy the patient's ability to initiate and control muscle movements and ultimately result in paralysis and respiratory death within 3-5 years. Patients with ALS have few treatment options that offer only limited effectiveness. We are designing a new class of oral drugs to combat motor neuron death while preserving function. Our efforts represent significant steps towards the development of a novel treatment for ALS and related NDs.