Microtubules in Spinal Cord Injury: From Cytoskeletal Dysregulation to Therapeutic Regeneration

ABSTRACT

Spinal cord injury (SCI) triggers an immediate and sustained disruption of the composition and organization of the neuronal cytoskeleton. Radical alterations in axonal and dendritic microtubules characterize both the acute injury phase and the protracted recovery period. For decades, researchers have sought to correct these microtubule defects as a therapeutic strategy to encourage axonal regeneration, collateral sprouting, and the functional rewiring of neuronal circuits. Recent studies have demonstrated that taxol and related microtubule‐active drugs improve outcomes in rodent models. These benefits are achieved by preventing microtubule depolymerization, stabilizing existing polymers, and promoting new assembly within both afflicted neurons and the glial cells essential for repair. While these findings highlight the therapeutic potential of microtubule‐based interventions, we posit that successful clinical translation necessitates a more sophisticated approach rooted in the growing knowledge of microtubule‐related proteins and their intricate regulatory mechanisms. This review evaluates progress in this arena, specifically examining the microtubule interactome network that includes structural microtubule‐associated proteins (MAPs) such as Tau, MAP1A, MAP1B, MAP2, and MAP6, as well as the stathmin family, plus‐end tracking proteins, and microtubule‐severing proteins such as fidgetin and spastin. In addition, we analyze the contribution of molecular motor proteins and regulatory MAPs, including CRMP2 and CRMP4, as well as upstream transcription factors governing their expression. Finally, we address convergent regulation through kinases such as GSK3β and CDK5, which represent a central mechanistic axis linking injury signaling to cytoskeletal failure. By integrating data from studies on development and regeneration into a unified mechanistic model, we provide a framework for microtubule‐based therapeutics for SCI.

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