Physiological and Pathological Roles and Targets of DLK/JNK signaling in distal axons

Axonal integrity is critical for nervous system function. After acute axonal injury, and in several neuropathological conditions, dual leucine-zipper kinase (DLK) signals via downstream c-Jun N- terminal kinases (JNKs) to convey signals from sites of axonal damage back to neuronal cell bodies. Proteins that are phosphorylated in response to such DLK/JNK pathway retrograde signaling, which include an array of transcription factors, are reasonably well understood. In contrast, although DLK and JNK also control the programmed self-destruction (Wallerian degeneration: WD) of damaged distal axons, axonal substrates of DLK/JNK that drive WD are far less clear. Moreover, recent studies suggest that basal DLK/JNK activity also maintains the integrity of healthy, undamaged distal axons. Again, though, the relevant DLK/JNK substrate(s) are unclear. This proposal builds on our comprehensive, unbiased phosphoproteomic identification of DLK substrates in healthy and damaged distal axons to provide unprecedented insights into these distinct roles of DLK/JNK signaling. In Aim 1 we will determine whether phosphorylation of the microtubule destabilizer Stathmin-1 is the master regulatory step that underlies DLK-dependent regulation of healthy axons. In Aim 2, we will build on our identification of an unexpected, widespread program of axonal dephosphorylation triggered by DLK in damaged axons. We will identify the functional consequences of this program for degradation of specific axonal proteins and for WD. This study will yield new insights into mechanisms that govern the balance between axonal integrity and degeneration and may identify new therapeutic targets to preserve axonal function in an array of neuropathological conditions Project Number: 1R21NS149559-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Gareth Thomas | Institution: TEMPLE UNIV OF THE COMMONWEALTH, PHILADELPHIA, PA | Award Amount: $435,875 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 AN-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11387968