Neuron survival and regeneration of neuronal axon connections after stroke is limited but essential for improving recovery of neurological function. Investigators from UCLA have identified new molecular pathways to promote post-stroke recovery by studying a mouse model lacking the gene SARM1 with axons that are inherently resistant to Wallerian degeneration or “dying back” after injury. In this study, they report that SARM1-deficient mice display greater preservation of axons after ischemic stroke and that neurons damaged by stroke show greater survival in the absence of SARM1. They also profile the changes in gene expression after stroke, comparing mice with normal levels of SARM1 and those without. This gene expression profile will help to identify a transcriptional “signature” that can be mimicked in drug treatment strategies to optimize neuron survival and connections in the stroke-injured brain.
Full abstract, to be presented at the American Neurological Association 2019 Annual Meeting (October 13-15 in St. Louis):
Absence of Sarm1 Promotes Axonal and Neuronal Survival after Stroke
Jack Wang, MD/PhD1, Brian Toh, B.S.2, Yutaro Komuro, PhD2, Jason D. Hinman, MD/PhD2. 1Stanford University, Palo Alto, CA, USA, 2University of California Los Angeles, Los Angeles, CA, USA.
The survival of neurons and the regeneration of neuronal connections after stroke is limited yet critical to enhancing recovery. Characterizing the molecular pathways that drive these regenerative phenomena may be achieved by studying models with inherent resistance to neuronal injury. Genetic deletion of SARM1 has been shown to prevent Wallerian axonal degeneration after traumatic axonal injury. In this study, we utilized SARM1 knockout mice in a mouse model of subcortical white matter stroke to determine rates of axonal survival after stroke and characterize the role of SARM1 in promoting neuronal survival and regeneration after stroke. Compared to wild-type mice, SARM1 knockout animals demonstrate enhanced axonal survival despite stroke injury. Persistent axonal survival is present 7 days after stroke but is maintained up to 28 days after stroke. In addition to its effect on axonal survival, SARM1 knockout conveys enhanced survival of stroke-injured cortical neurons that lasts up to one month after stroke. Using magnetic and fluorescent cell sorting approaches, we captured stroke-injured NCAM+ cortical neurons from wild-type and SARM1 knockout mice and identified the transcriptional changes between these two neuronal populations using RNA-sequencing. In stroke-injured cortical neurons, genetic deletion of SARM1 drives a unique reparative gene expression profile with 283 up- and 621 down-regulated genes. Gene ontology analysis identifies specific clusters of gene expression programs in stroke-injured SARM1 knockout neurons that promote regenerative pathways necessary for stroke recovery including axonal outgrowth, neuronal development, and synaptic formation. Genetic and drug approaches that mimic this transcriptional signature observed in stroke-injured cortical neurons from SARM1 knockout mice can identify new therapeutic strategies to promote both neuroprotection and neural repair after stroke.
All abstracts from ANA2019 will be available under embargo starting October 4. Contact Katherine Pflaumer (firstname.lastname@example.org) for full meeting abstracts, and for call-in information for the ANA2019 Media Roundtable (Oct. 15, 11 a.m. US Central).