Unraveling the role of Stathmin-2 palmitoylation in maintaining axon health
Creators: name: Thornburg-Suresh, Emma Jane Collene
Publisher: name: University of Iowa
Year: 2024
Subjects: ALS
axon
DLK
Stathmin-2

description: The axon is a specialized extension of the neuron, responsible for carrying chemical and electrical signals across the nervous system. Axons reach incredible distances in the body, causing many of them to live in extreme isolation from the cell body. This extreme length makes axons especially sensitive to physical and chemical injuries as well as disease. Axon degeneration is an early and sometimes initiating event in many neurodegenerative diseases. Therefore, understanding how axons survive over an organism’s lifetime is essential to prevent axon degeneration from occurring. Here, I investigate the role of Stathmin-2 (Stmn2), a microtubule regulatory protein, in the maintenance of axon health. Stmn2 is a crucial player in amyotrophic lateral sclerosis (ALS) pathology. Stmn2 protein levels are significantly reduced in patients with ALS. Loss of Stmn2 in mouse models recapitulates the sensory and motor neuropathies observed in ALS patients. Furthermore, maintaining high levels of Stmn2 in the axon following injury prevents axon degeneration. Taken together, these findings reinforce a role for Stmn2 in axon integrity; however, the mechanism remains unclear. In this dissertation I reveal that palmitoylation of Stmn2 is required for its role in axon integrity.
description: I discovered that Stmn2 palmitoylation is required for Stmn2’s axon protective effects. Furthermore, I discovered that another membrane targeted Stathmin (Stmn3) has axon protective effects that are also palmitoylation-dependent. Palmitoylation and membrane association of these Stathmin family members targets them for degradation by the pro-degenerative signaling pathway involving Dual Leucine Zipper Kinase (DLK). Altogether, these results show that palmitoylation is required for Stmn2’s axon protective activity and connects to a pro-degenerative signaling pathway involved in a myriad of neurodegenerative diseases.
description: I also began to characterize Stmn2-containing vesicles. Stmn2 does not colocalize with known vesicular markers, therefore, characterization of this vesicle population will have important insights into axon health. Relocalization of Stmn2 to a separate vesicle population diminishes its axon protective effects, further providing support to the idea that Stmn2-containing vesicles have a specific function in axon maintenance. Furthermore, comigration experiments revealed that Stmn2 co-traffics with Stmn3 and DLK in sensory neuron axons, but only partially co-traffics with the axon maintenance factor Nmnat2. These results suggest there is a Stathmin-enriched vesicle population involved in axon integrity that is directly tied to the pro-degenerative signaling pathway involving DLK. Interestingly, inhibition of DLK alters Stmn2 vesicle dynamics.
description: In this dissertation I show that Stmn2 palmitoylation is a requirement for Stmn2’s activity in axon maintenance. Future work will expand on the characterization of Stmn2-containing vesicles using proximity labeling assays like BioID and a candidate approach. Future work will also address the connections between Stmn2 palmitoylation, DLK signaling, and microtubule dynamics. Understanding the mechanism for Stmn2 in axon integrity is essential as its being targeted for drug therapies in ALS. Overall this work further elucidates mechanisms involved in the maintenance of axon health.