Diaz Paloma J, Shi Qian, McNeish Priscilla Y, Banerjee Swati
Department of Cellular and Integrative Physiology, University of Texas Health Science Center San Antonio, Joe R. and Teresa Lozano Long School of Medicine, San Antonio, Texas, USA.
Center for Biomedical Neuroscience, University of Texas Health Science Center San Antonio, Joe R. and Teresa Lozano Long School of Medicine, San Antonio, Texas, USA.
J Neurosci Res. 2025 May;103(5):e70044. doi: 10.1002/jnr.70044.
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.
微管蛋白聚合促进蛋白（TPPPs）在物种间高度保守，但人们对其了解仍然有限。人类有三个TPPP基因，而在果蝇和秀丽隐杆线虫等无脊椎动物中只有一个同源的TPPP基因。人类TPPP（TPPP1/p25/p25α）在大脑中富集，与无脊椎动物的TPPPs具有序列相似性。TPPP/p25与微管相关，在微管动力学、成束和聚合过程中起关键作用，从而稳定微管网络。这对于细胞骨架组织以及神经元和神经胶质细胞的正常功能至关重要，包括轴突生长、再生、迁移、运输、突触形成和轴突髓鞘形成。然而，研究还发现，除了其在细胞质/微管中的定位外，TPPP/p25还存在于其他亚细胞区室，包括线粒体和细胞核，这凸显了其存在其他新功能。在分子水平上，TPPP/p25预计以一种内在无序的蛋白质形式存在，并与神经和神经退行性疾病有关，包括帕金森病及相关疾病和多发性硬化症。在本文中，我们对TPPP/p25进行了全面概述，强调了其进化保守性、细胞和亚细胞定位、在神经系统中已确定和新出现的功能、相互作用的伙伴、与人类神经疾病潜在的临床相关性，并以未解决的问题和未来的研究领域作为总结。
