Dr. Casper Hoogenraad
Vice President and Senior Fellow
Head of Neuroscience Research, Genentech
In many neurodegenerative diseases, axons fail long before neuronal cell bodies die, yet the molecular mechanisms that link early axonal injury to subsequent brain inflammation remain poorly understood. In this talk, I will discuss how Sterile alpha and TIR motif containing 1 (SARM1), an inducible NADase, functions as a central regulator of axon degeneration across diverse forms of neuronal stress. Using multiple experimental paradigms, we find that SARM1 activation is highly compartmentalized within neurons, with distinct spatial patterns that depend on the nature of the insult. Certain stressors trigger localized SARM1 activation within axons, whereas others induce more global activation, leading to broader neuronal degeneration. Axonal breakdown driven by SARM1 activation is accompanied by the regulated release of neurofilament light (NfL). While NfL is widely used as a clinical biomarker of neurodegeneration, our findings demonstrate that released NfL is not merely a passive byproduct of neuronal damage. Instead, extracellular NfL actively engages microglia and macrophages, promoting neuroinflammatory responses within the brain. Together, these findings establish a mechanistic link between compartment-specific axon degeneration and immune activation, and they reveal new therapeutic considerations for targeting axonal pathology and inflammation in neurodegenerative disease.
Lena Nechayeva
Email