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Drosophila tubulin polymerization promoting protein mutants reveal pathological correlates relevant to human Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disorder with no known cure. PD is characterized by locomotion deficits, nigrostriatal dopaminergic neuronal loss, mitochondrial dysfunctions and formation of α-Synuclein aggregates. A well-conserved and less understood family of Tubulin Polymerization Promoting Proteins (TPPP) is also implicated in PD and related disorders, where TPPP exists in pathological aggregates in neurons in patient brains. However, there are no in vivo studies on mammalian TPPP to understand the genetics and neuropathology linking TPPP aggregation or neurotoxicity to PD. Recently, we discovered the only Drosophila homolog of human TPPP named Ringmaker (Ringer). Here, we report that adult ringer mutants display progressive locomotor disabilities, reduced lifespan and neurodegeneration. Importantly, our findings reveal that Ringer is associated with mitochondria and ringer mutants have mitochondrial structural damage and dysfunctions. Adult ringer mutants also display progressive loss of dopaminergic neurons. Together, these phenotypes of ringer mutants recapitulate some of the salient features of human PD patients, thus allowing us to utilize ringer mutants as a fly model relevant to PD, and further explore its genetic and molecular underpinnings to gain insights into the role of human TPPP in PD.

SUBMITTER: Xie J

PROVIDER: S-EPMC8245532 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tubulin polymerization-promoting protein (TPPP/p25) is critical for oligodendrocyte differentiation.

Project description:TPPP/p25, a recently identified tubulin polymerization-promoting protein (TPPP), is expressed mainly in myelinating oligodendrocytes of the CNS. Here, we show that TPPP/p25 is strongly upregulated during the differentiation of primary oligodendrocyte cells as well as the CG-4 cell line. The microRNA expression profile of CG-4 cells before and after induction of differentiation was established and revealed differential regulation of a limited subset of microRNAs. miR-206, a microRNA predicted to target TPPP/p25, was not detected in oligodendrocytes. Overexpression of miR-206 led to downregulation of TPPP/p25 resulting in inhibition of differentiation. Transfection of siRNAs against TPPP/p25 also inhibited cell differentiation and promoted cell proliferation, providing evidence for an important role of TPPP/p25 during oligodendrogenesis. These results support an essential role for TPPP/p25 in oligodendrocyte differentiation likely via rearrangement of the microtubule system during the process elongation prior to the onset of myelination.

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Tubulin polymerization promoting protein 1 (TPPP1): A DNA-damage induced microtubule regulatory gene.

Project description:The eukaryotic cell cycle relies heavily on the mechanical forces vested by the dynamic rearrangement of the microtubule (MT) network. Tubulin Polymerization promoting Protein 1 (TPPP1) alters MT dynamics by driving MT polymerization as well as stabilization, via increasing MT acetylation. It increases MT rigidity, which results in reduced cell proliferation through downregulation of G1/S-phase and mitosis to G1-phase cell cycle transitioning. In this communication, we provide further evidence that TPPP1 may be an important regulator of genomic homeostasis. Our preliminary data show that long-term TPPP1 overexpression reduces cell viability via induction of apoptotic cell death pathways. Moreover, induction of DNA-damage results in increased TPPP1 expression, which is inhibited in the absence of expression of the tumor suppressor p53.

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The Role of Tubulin Polymerization-Promoting Protein2 (TPPP2) in Spermatogenesis: A Narrative Review

Project description: Not available

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Tubulin Polymerization Promoting Protein, Ringmaker, and MAP1B Homolog Futsch Coordinate Microtubule Organization and Synaptic Growth.

Project description:Drosophila Ringmaker (Ringer) is homologous to the human Tubulin Polymerization Promoting Proteins (TPPPs) that are implicated in the stabilization and bundling of microtubules (MTs) that are particularly important for neurons and are also implicated in synaptic organization and plasticity. No in vivo functional data exist that have addressed the role of TPPP in synapse organization in any system. Here, we present the phenotypic and functional characterization of ringer mutants during Drosophila larval neuromuscular junction (NMJ) synaptic development. ringer mutants show reduced synaptic growth and transmission and display phenotypic similarities and genetic interactions with the Drosophila homolog of vertebrate Microtubule Associated Protein (MAP)1B, futsch. Immunohistochemical and biochemical analyses show that individual and combined loss of Ringer and Futsch cause a significant reduction in MT loops at the NMJs and reduced acetylated-tubulin levels. Presynaptic over-expression of Ringer and Futsch causes elevated levels of acetylated-tubulin and significant increase in NMJ MT loops. These results indicate that Ringer and Futsch regulate synaptic MT organization in addition to synaptic growth. Together our findings may inform studies on the close mammalian homolog, TPPP, and provide insights into the role of MTs and associated proteins in synapse growth and organization.

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Tubulin Polymerization Promoting Proteins (TPPPs) of Aphelidiomycota: Correlation between the Incidence of p25alpha Domain and the Eukaryotic Flagellum.

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Ampelopsin-sodium induces apoptosis in human lung adenocarcinoma cell lines by promoting tubulin polymerization <i>in vitro</i>.

Project description:Previous studies have demonstrated that ampelopsin (AMP), a type of flavonoid isolated from the stems and leaves of Ampelopsis grossedentata, exhibits anti-cancer activity in various types of cancer. Conversion of AMP into its sodium salt (AMP-Na) conferred enhanced solubility and stability to it. The present study aimed to evaluate the anti-cancer activity of AMP-Na in human lung adenocarcinoma cell lines and to investigate its mechanisms of action. Cell proliferation and viability were assessed by MTT and colony formation assays, and cell migration was determined using a scratch wound healing assay. The cell cycle distribution, apoptosis rate and tubulin immunofluorescence intensity were analyzed using flow cytometry, the cell ultra-microstructure was examined using transmission electron microscopy and the accumulation of tubulin was determined using laser confocal microscopy. The results demonstrated that AMP-Na significantly inhibited the proliferation, clonogenicity and migration of human lung adenocarcinoma cells. Furthermore, AMP-Na induced SPC-A-1 cell apoptosis, and promoted tubulin polymerization. The results suggested that the underlying mechanisms of AMP-Na may involve targeting of microtubules and tubulin polymerization to subsequently disrupt mitosis and induce cell cycle arrest at the S-phase.

| S-EPMC6540484 | biostudies-literature

miR-31 mutants reveal continuous glial homeostasis in the adult Drosophila brain.

Project description:The study of adult neural cell production has concentrated on neurogenesis. The mechanisms controlling adult gliogenesis are still poorly understood. Here, we provide evidence for a homeostatic process that maintains the population of glial cells in the Drosophila adult brain. Flies lacking microRNA miR-31a start adult life with a normal complement of glia, but transiently lose glia due to apoptosis. miR-31a expression identifies a subset of predominantly gliogenic adult neural progenitor cells. Failure to limit expression of the predicted E3 ubiquitin ligase, Rchy1, in these cells results in glial loss. After an initial decline in young adults, glial numbers recovered due to compensatory overproduction of new glia by adult progenitor cells, indicating an unexpected plasticity of the Drosophila nervous system. Experimentally induced ablation of glia was also followed by recovery of glia over time. These studies provide evidence for a homeostatic mechanism that maintains the number of glia in the adult fly brain.

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Knockdown of Tubulin Polymerization Promoting Protein Family Member 3 inhibits cell proliferation and invasion in human colorectal cancer.

Project description:Tubulin Polymerization Promoting Protein Family Member 3 (TPPP3), a member of the TPPP protein family, has been reported to play important roles in initiation and progression of human cancers. However, the expression and underlying function of TPPP3 in colorectal cancer (CRC) have not yet been fully clarified. In this study, the mRNA and protein levels of TPPP3 in 96 clinical CRC specimens were determined by RT-PCR and immunohistochemistry. The relation between TPPP3 expression and clinicopathologic characteristics and overall survival (OS) were evaluated. Further experiments showed that knockdown of TPPP3 inhibited cell proliferation, migration and invasion and induced cell apoptosis in vitro. In addition, TPPP3 silencing resulted in a decrease of angiogenesis and S phase fraction. Thus, our results suggested that TPPP3 played an important role in CRC progress and might serve as novel therapeutic target for CRC treatment.

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Highly potent triazole-based tubulin polymerization inhibitors.

Project description:We describe the synthesis and biological evaluation of a series of tubulin polymerization inhibitors that contain the 1,2,4-triazole ring to retain the bioactive configuration afforded by the cis double bond in combretastatin A-4 (CA-4). Several of the subject compounds exhibited potent tubulin polymerization inhibitory activity as well as cytotoxicity against a variety of cancer cells including multi-drug-resistant (MDR) cancer cell lines. Attachment of the N-methyl-5-indolyl moiety to the 1,2,4-triazole core, as exemplified by compound 7, conferred optimal properties among this series. Computer docking and molecular simulations of 7 inside the colchicine binding site of tubulin enabled identification of residues most likely to interact strongly with these inhibitors and explain their potent anti-tubulin activity and cytotoxicity. It is hoped that results presented here will stimulate further examination of these substituted 1,2,4-triazoles as potential anti-cancer therapeutic agents.

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Heterogeneous Tau-Tubulin Complexes Accelerate Microtubule Polymerization.

Project description:Tau is an intrinsically disordered protein with a central role in the pathology of a number of neurodegenerative diseases. Tau normally functions to stabilize neuronal microtubules, although the mechanism underlying this function is not well understood. Of note is that the interaction between tau and soluble tubulin, which has implications both in understanding tau function as well as its role in disease, is underexplored. Here we investigate the relationship between heterogeneity in tau-tubulin complexes and tau function. Specifically, we created a series of truncated and scrambled tau constructs and characterized the size and heterogeneity of the tau-tubulin complexes formed under nonpolymerizing conditions. Function of the constructs was verified by tubulin polymerization assays. We find that, surprisingly, the pseudo-repeat region of tau, which flanks the core microtubule-binding domain of tau, contributes largely to the formation of large, heterogeneous tau tubulin complexes; additional independent tubulin binding sites exist in repeats two and three of the microtubule binding domain. Of particular interest is that we find positive correlation between the size and heterogeneity of the complexes and rate of tau-promoted microtubule polymerization. We propose that tau-tubulin can be described as a "fuzzy" complex, and our results demonstrate the importance of heterogeneous complex formation in tau function. This work provides fundamental insights into the functional mechanism of tau, and more broadly underscores the relevance of heterogeneous and dynamic complexes in the functions of intrinsically disordered proteins.

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