The long-term goal of this project is to define molecular mechanisms by which long-distance signals are conveyed in axons. Retrograde signals from distal axons to neuronal nuclei are critical to activate transcriptional programs both during neurodevelopment and following nerve injury. These retrograde signals involve physical protein transport, but several retrograde signaling proteins are predicted to be soluble and diffusible and it is unclear how they convey long distance directional signals. This project seeks to test the novel hypothesis that the protein-lipid modification palmitoylation allows otherwise soluble signaling proteins to 'hitchhike' on trafficking vesicles and thus convey retrograde signals. Our preliminary studies support this hypothesis and suggest that direct palmitoylation is essential for retrograde signaling by Dual Leucine-zipper Kinase (DLK) in response to injury.
Aim 1 of this proposal will define the cellular and molecular basis for this finding, in particularby testing the novel hypothesis that palmitoylation is a unique 'dual control' mechanism that regulates both DLK localization and kinase activity. We will then define the importance of palmitoylation for DLK's 'downstream' functional roles in axonal regeneration post-injury.
Aim 2 addresses how palmitoylation regulates signaling by a second pathway involving Janus Kinase (JAK) and JAK's substrate Signal Transducer and Activator of Transcription-3 (STAT3). Importantly, JAK-STAT3 signaling requires dynamic relocalization of these proteins from their steady-state locations in response to extracellular stimuli.
This Aim will thus determine whether palmitoylation is broadly required for retrograde signaling and will also define the importance of stimulus-dependent palmitoylation for dynamic retrograde trafficking.
Aim 3 seeks to identify the palmitoyl acyltransferases (PATs) that control palmitoylation of retrograde signaling proteins, focusing on whether the axonally-enriched PATs DHHC5 and DHHC8 are key regulators of JAK/STAT3's 'upstream' receptor gp130. The overall impact of this proposal will be to define a novel molecular mechanism that is critical to convey axonal retrograde signals. The focus of this work on responses to axonal injury could lead to new therapies to improve regenerative growth, while the discoveries made should also enhance our broader understanding of axon development and of neuropathological conditions linked to impaired axonal trafficking.
Long distance signaling and trafficking of proteins in neuronal axons is important for neurodevelopment and for responses to nerve injury, while impaired axonal trafficking is a hallmark of many neurodegenerative disorders. This work focuses on how a protein-lipid modification called palmitoylation regulates the transport and activity of axonal signaling enzymes that are critical for injury responses. The proposed research will define a novel mechanism via which nerve injury signals are conveyed, potentially revealing new strategies to enhance regenerative growth. In addition, this work could enhance our understanding of a broad range of neurodegenerative conditions in which axonal trafficking and signaling is impaired.
| Holland, Sabrina M; Thomas, Gareth M (2017) Roles of palmitoylation in axon growth, degeneration and regeneration. J Neurosci Res 95:1528-1539 |
| Niu, Jingwen (2017) Neurodegeneration and regeneration. J Neurosci Res 95:1525-1527 |
| Holland, Sabrina M; Collura, Kaitlin M; Ketschek, Andrea et al. (2016) Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling. Proc Natl Acad Sci U S A 113:763-8 |
| Montersino, Audrey; Thomas, Gareth M (2015) Slippery signaling: Palmitoylation-dependent control of neuronal kinase localization and activity. Mol Membr Biol 32:179-88 |
