Molecular mechanisms of neuronal cell death

A central challenge in neurobiology is understanding how to protect the brain from Alzheimer’s disease. Increasing evidence points to a critical link between synaptic function and neurodegeneration. Yet, the molecular mechanisms underlying this relationship remain poorly defined, largely because neurodegenerative diseases are highly context dependent: factors such as genetic predisposition and age strongly influence the onset and progression of neurodegeneration and cell death. Uncovering context specific mechanisms of disease demands that we investigate novel models of neurodegeneration and cell death in multiple types of animals. Such models offer untapped insights into the molecular pathways that drive or prevent neuronal decline and hold promise for informing innovative candidate therapeutic directions for neurodegenerative disease. We have identified multiple suppressors of neurotoxicity in aged animals using two novel models of age-related neurotoxicity that induce axon degeneration and cell death: one is caused by overexpression of a pore-modified ionotropic acetylcholine receptor subunit that produces excess synaptic activation, and the other is caused by prolonged oxidative stress due to paraquat exposure. Our investigations are performed in C. elegans, which have a relatively simple nervous system, are highly genetically tractable, and have been successfully used to identify conserved mechanisms of neurodegeneration, oxidative stress and synapse function. We are leveraging these strengths to answer the critical question of how context specific molecular mechanisms protect against neurodegeneration. Specifically, we will 1) determine how TIR-1/SARM1, a key and conserved regulator of axon degeneration, instead protects against persistent excitotoxicity- and oxidative stress-induced axon degeneration and cell death, and 2) determine how 10 mutations identified from an unbiased forward genetic screen protect against neurotoxicity. By identifying and characterizing molecular pathways that preserve neuronal integrity, our findings will advance our understanding of context-specific neuroprotection and potentially inform strategies to combat the devastating neurodegeneration seen in Alzheimer’s disease. Project Number: 1R21AG093537-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Alexandra Byrne (+1 co-PI) | Institution: UNIV OF MASSACHUSETTS MED SCH WORCESTER, WORCESTER, MA | Award Amount: $452,783 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BN-F (92)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11374236