Uncovering Rules to Sustain Neurons' Long Lives: Signaling Redundancy and Resiliency at the Onset of Neurodegenerative Disease

Abstract

Our laboratory has been experimentally asking if there is a molecular logic that sustains neuronal survival as the brain is confronted with onset and/ or progression of neurodegenerations. We found that under imminent homeostasis disturbance, the brain activates the production of mediators of cell integrity and function, which includes the elovanoids (ELVs). They are formed from very long-chain polyunsaturated fatty acids (C 32-34) synthesized by neuronal-specific ELOVL4. Mutations of the gene that encodes this enzyme cause, among other pathologies, vision loss, seizures, and mental retardation. ELVs protect neurons by upregulating pro-survival and downregulating pro-apoptotic protein abundance. Also, ELVs enhance deacetylase Sirtuin 1, which modulates longevity signaling; E3 ubiquitin ligase (Iduna), and transcriptional regulator Prohibitin type 2. The ELV synthesis pathways are downregulated in Alzheimer’s models and in specific retinal cells of age-related macular degeneration patients. Using limited proteolysis/MS, we found that ELV-N34 selectively modulates TNXRD1 (from thioredoxin, an NADPH/FAD redox- effector that sustains homeostasis) underling its protection.