Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary.
Department of Immunology and Biotechnology, Medical School, University of Pécs, 7624 Pécs, Hungary.
Cells. 2022 Sep 27;11(19):3025. doi: 10.3390/cells11193025.
Parkinson's disease is characterized by locomotion deficits, dopaminergic neuronal loss and alpha-synuclein (SYN) aggregates; the Tubulin Polymerization Promoting Protein (TPPP/p25 or TPPP1) is also implicated in these processes. The moonlighting and chameleon TPPP1 modulates the dynamics/stability of the multifunctional microtubule network by promoting its acetylation and bundling. Previously, we identified the microtubule-associated TPPP3, a homologue of TPPP1 lacking its N-terminus; however, its involvement in physiological or pathological processes was not elucidated. In this work, we have shown the modulatory role of TPPP3, similarly to TPPP1, in microtubule organization, as well as its homo- and hetero-associations with TPPP1. TPPP3, in contrast to TPPP1, virtually does not bind to SYN; consequently, it does not promote SYN aggregation. Its anti-aggregative potency is achieved by counteracting the formation of the TPPP1-SYN pathological complex/aggregation leading to Parkinsonism. The interactions of TPPP3 have been determined and quantified in vitro with recombinant human proteins, cell extracts and in living human cells using different methods including bifunctional fluorescence complementation. The tight association of TPPP3 with TPPP1, but not with SYN, may ensure a unique mechanism for its inhibitory effect. TPPP3 or its selected fragments may become a leading agent for developing anti-Parkinson agents.
帕金森病的特征是运动缺陷、多巴胺能神经元丧失和α-突触核蛋白（SYN）聚集体；微管聚合促进蛋白（TPPP/p25 或 TPPP1）也与这些过程有关。多功能微管网络的动态/稳定性通过促进其乙酰化和束集来调节月光和变色龙 TPPP1。先前，我们鉴定了微管相关的 TPPP3，它是缺乏 N 端的 TPPP1 的同源物；然而，其在生理或病理过程中的参与尚未阐明。在这项工作中，我们表明 TPPP3 与 TPPP1 相似，在微管组织中具有调节作用，以及其与 TPPP1 的同型和异型缔合。与 TPPP1 相比，TPPP3 几乎不与 SYN 结合；因此，它不会促进 SYN 聚集。它的抗聚集能力是通过拮抗 TPPP1-SYN 病理性复合物/聚集的形成来实现的，这导致帕金森病。使用不同的方法，包括双荧光互补，已经在体外确定和量化了 TPPP3 与重组人蛋白、细胞提取物和活的人类细胞之间的相互作用。TPPP3 与 TPPP1 的紧密结合，而不是与 SYN 的结合，可能确保了其抑制作用的独特机制。TPPP3 或其选择的片段可能成为开发抗帕金森药物的主导剂。
