Tubulin Polymerization Promoting Proteins (TPPPs) are highly conserved across species but remain poorly understood. There are three TPPP genes in humans, with only one homologous TPPP gene in invertebrates, such as Drosophila and C. elegans. The human TPPP (TPPP1/p25/p25α) is enriched in the brain and shares sequence similarities with the invertebrate TPPPs. TPPP/p25 associates with microtubules and plays a pivotal role in microtubule dynamics, bundling, and polymerization, thereby stabilizing the microtubular network. This is essential for cytoskeletal organization and proper functioning of neurons and glial cells, including axonal growth, regeneration, migration, trafficking, synapse formation, and myelination of axons. However, studies have also uncovered that besides its cytoplasmic/microtubular localization, TPPP/p25 is present in other subcellular compartments, including the mitochondria and nucleus, underscoring the presence of additional novel functions. At the molecular level, TPPP/p25 is predicted to exist as an intrinsically disordered protein and is implicated in neurological and neurodegenerative disorders, including Parkinson's and related disorders and Multiple Sclerosis. In this article, we provide a comprehensive overview of TPPP/p25, highlighting its evolutionary conservation, cellular and subcellular localization, established and emerging functions in the nervous system, interacting partners, potential clinical relevance to human neurological disorders, and conclude with unresolved questions and future areas of study.
Keywords: CNS; ensheathment; microtubule; mitochondria; α‐synucleinopathies.
© 2025 The Author(s). Journal of Neuroscience Research published by Wiley Periodicals LLC.