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#microtubule

5 posts1 participant5 posts today
Rxiv cytoskeleton

📰 "Circadian timing and entrainment properties of the SCN pacemaker in the PS19 mouse model of tau pathology"
doi.org/doi:10.1101/2025.06.06
pubmed.ncbi.nlm.nih.gov/406421
#Microtubule

bioRxiv · Circadian timing and entrainment properties of the SCN pacemaker in the PS19 mouse model of tau pathologyTauopathies are a group of neurodegenerative disorders caused by the misfolded microtubule-associated protein tau (MAPT), leading to its abnormal accumulation and hyperphosphorylation, and resulting in neuronal dysfunction and death. Tauopathy patients also experience disruptions to circadian rhythms of behavior and sleep. The connection between tau pathology and circadian dysfunction is not well understood, especially regarding the role of the suprachiasmatic nucleus (SCN), the brain’s central circadian pacemaker. Here, we conducted histological and functional analyses of the SCN in the PS19 (Prnp-huMAPT*P301S) mouse model of tauopathy. The SCN of PS19 mice had accumulation of phosphorylated tau as early as 2 months of age, and tau pathology was detected in both major neuronal subpopulations of the SCN: VIPergic (core) and AVPergic (shell) neurons. To assess SCN timing and entrainment properties, daily locomotor activity was monitored in PS19 and wild-type (WT) mice from 3 to 11 months-of-age. Activity profiles, rates of re-entrainment to changes in the light/dark cycle, and intrinsic circadian timing properties were unchanged in PS19 mice compared to age-matched WT mice. Finally, profiling circadian gene expression in tau fibril-seeded SCN explants from PS19 and WT mice did not reveal differences in network-level oscillator properties. Together, these findings suggest that tau pathology within the SCN is not sufficient to trigger marked disruptions of core circadian timing mechanisms in this tauopathy model. Further, these results raise the possibility that circadian disruptions in tauopathies arise from dysfunction in SCN-gated output pathways or downstream clock-gated circuits rather than the SCN oscillator itself. ### Competing Interest Statement The authors have declared no competing interest. NIH, GM133032, AG065830
Rxiv cytoskeleton

📰 "Emergent microtubule properties in a model of filament turnover and nucleation"
arxiv.org/abs/2504.11466
#Physics.Bio-Ph #Microtubule #Q-Bio.Sc

arXiv logo
arXiv.orgEmergent microtubule properties in a model of filament turnover and nucleationMicrotubules (MTs) are dynamic protein filaments essential for intracellular organization and transport, particularly in long-lived cells such as neurons. The plus and minus ends of neuronal MTs switch between growth and shrinking phases, and the nucleation of new filaments is believed to be regulated in both healthy and injury conditions. We propose stochastic and deterministic mathematical models to investigate the impact of filament nucleation and length-regulation mechanisms on emergent properties such as MT lengths and numbers in living cells. We expand our stochastic continuous-time Markov chain model of filament dynamics to incorporate MT nucleation and capture realistic stochastic fluctuations in MT numbers and tubulin availability. We also propose a simplified partial differential equation (PDE) model, which allows for tractable analytical investigation into steady-state MT distributions under different nucleation and length-regulating mechanisms. We find that the stochastic and PDE modeling approaches show good agreement in predicted MT length distributions, and that both MT nucleation and the catastrophe rate of large-length MTs regulate MT length distributions. In both frameworks, multiple mechanistic combinations achieve the same average MT length. The models proposed can predict parameter regimes where the system is scarce in tubulin, the building block of MTs, and suggest that low filament nucleation regimes are characterized by high variation in MT lengths, while high nucleation regimes drive high variation in MT numbers. These mathematical frameworks have the potential to improve our understanding of MT regulation in both healthy and injured neurons.
Rxiv cytoskeleton

📰 "Targeting Aurora kinases as essential cell cycle regulators to deliver multi-stage antimalarials against Plasmodium falciparum"
biorxiv.org/content/10.1101/20
#Microtubule

bioRxiv · Targeting Aurora kinases as essential cell cycle regulators to deliver multi-stage antimalarials against Plasmodium falciparumKinases that play critical roles in the development and adaptation of Plasmodium falciparum present novel opportunities for chemotherapeutic intervention. Of particular interest are mitotic kinases that regulate the proliferation of the parasites by controlling nuclear division, segregation and cytokinesis. We evaluated the potential of human Aurora kinase (Aur) inhibitors to inhibit P. falciparum development by targeting members of the Aurora-related kinase (Ark) family in this parasite. Several human AurB inhibitors exhibited multistage potency (<250 nM) against all proliferative stages of parasite development, including asexual blood stages, liver schizonts and male gametes. Among the most potent compounds, hesperadin and AT83 exhibit >1000x selectivity towards the parasite without mammalian cell toxicity concerns. Importantly, we identified Pf Ark1 as the prime vulnerable Ark family member, with specific inhibition of Pf Ark1 as the primary target for hesperadin and the human anaplastic lymphoma kinase (ALK) inhibitor TAE684. Hesperadin′s whole-cell and protein activity validates it as a unique Pf Ark1 tool compound. Inhibition of Pf Ark1 results in the parasite′s inability to complete mitotic processes, presenting with unsegregated, multi-lobed nuclei caused by aberrant microtubule organization. This suggests that Pf Ark1 is the main Aur mitotic kinase in proliferative stages of Plasmodium , characterized by bifunctional AurA and B activity. This paves the way for drug discovery campaigns based on hesperadin targeting Pf Ark1. ### Competing Interest Statement The authors have declared no competing interest. Medicines for Malaria Venture, https://ror.org/00p9jf779, RD-19-001, RD-21-1003 National Research Foundation, 84627
Rxiv cytoskeleton

📰 "Micron-scale protein transport along microtubules by kinesin-driven shepherding"
doi.org/doi:10.1101/2025.06.28
pubmed.ncbi.nlm.nih.gov/406312
#Microtubule #Kinesin

bioRxiv · Micron-scale protein transport along microtubules by kinesin-driven shepherdingMicrotubule-based long-distance transport in eukaryotic cells typically involves the binding of cargo to motors such as highly processive kinesins for unidirectional transport. An open question is whether long-distance transport can occur by mechanisms that do not require specific motor-cargo interactions and high processivity. In addition to conventional cargo such as vesicles, kinesin also shuttles non-motor microtubule-associated proteins (MAPs) to microtubule ends. Computational modeling of a system of a motor and a MAP that do not bind directly with one another unexpectedly revealed the redistribution of the MAP to microtubule plus ends, suggesting an unconventional mode of protein transport. We recapitulated this phenomenon experimentally in a minimal in vitro system using a kinesin-1 protein (K401) and PRC1, a non-motor MAP that binds diffusively on microtubules and shows no detectable binding to K401. Single-molecule imaging revealed unidirectional streams of PRC1 molecules over micron distances along microtubules. Our findings suggest that a stoichiometric excess of K401 can act as a unidirectional barrier to PRC1 diffusion. This effectively “shepherds” PRC1 to microtubule plus end without conventional motor-cargo interactions. Remarkably, we found that shepherding occurs with low kinesin processivity. Shepherding by kinesin-1 was also observed with another MAP. These findings reveal a new mechanism of transport for microtubule-bound cargo that does not require high-affinity motor-cargo binding and motor processivity, two principles conventionally invoked for cellular transport. SIGNIFICANCE STATEMENT The textbook model of intracellular transport on microtubules involves the direct binding of cargo to processive motors, which then carry the cargo over long distances. Here, we combine computational modeling and single-molecule imaging to identify an alternative mode of protein transport by which non-motor microtubule associated proteins (MAPs) can be transported over microns without direct interactions with motor proteins. We show that “protein shepherding” results from kinesin molecules biasing the diffusion of non-motor MAPs. The unconventional transport mechanism revealed here, which does not require direct motor-cargo interaction or high motor processivity, broadens our understanding of the physical mechanisms that enhance microtubule-based cargo transport in cells. ### Competing Interest Statement The authors have declared no competing interest. National Science Foundation, https://ror.org/021nxhr62, DMR1725065, ACI-1532235, ACI-1532236 National Institutes of Health, 5R01GM124371, 1R01GM155215
Rxiv cytoskeleton

📰 "Conformational flexibility of tubulin dimers regulates the transitions of microtubule dynamic instability"
doi.org/doi:10.1101/2025.06.30
pubmed.ncbi.nlm.nih.gov/406312
#Microtubule

bioRxiv · Conformational flexibility of tubulin dimers regulates the transitions of microtubule dynamic instabilityMicrotubules are highly conserved polymers of αβ-tubulin dimers that undergo dynamic instability. While dynamic instability is conserved across eukaryotes, many of its associated conformational changes, like lattice compaction and twist, are not. Tubulin dimers sample multiple conformations in solution and undergo conformational changes during polymerization; the rate and extent of these changes describes their “conformational flexibility.” Here, we investigate the relationship between the conformational flexibility of tubulins and the dynamic phenotypes of the microtubules they produce with a comparative study of Drosophila melanogaster tubulin (Dm-Tb) and Bos taurus brain tubulin (Bt-Tb). While these tubulins share high sequence and structural similarity, their microtubules display divergent dynamic phenotypes in vitro , with altered transition frequencies between phases of growth and shrinkage. Dm-Tb microtubules showed drastically longer lifetimes, lower barriers to nucleation, and a high rescue frequency, while maintaining a similar growth rate to Bt-Tb microtubules. 3D reconstruction of mature Dm-Tb microtubules showed high structural conservation with mammalian microtubules. However, when we performed molecular dynamics simulations of free tubulin dimers, we found Dm-Tb to be more rigid and adopt fewer conformational states than Bt-Tb. Biochemical characterizations experimentally confirmed this finding, leading us to hypothesize that differences in the conformational flexibility of tubulins may tune the frequency of transitions between the dynamic phases of microtubules, thereby altering their stability and overall dynamic phenotypes. ### Competing Interest Statement The authors have declared no competing interest. Fonds de Recherche du Québec - Santé, https://ror.org/02eqrsj93, 288558 Canada Foundation for Innovation, 33122 National Institutes of Health, https://ror.org/01cwqze88, S10OD020011, R01GM141119 Fonds de Recherche du Québec – Nature et Technologies, https://doi.org/10.69777/317016 McGill University, https://ror.org/01pxwe438 University of Michigan–Ann Arbor, https://ror.org/00jmfr291 Canadian Institutes of Health Research, https://ror.org/01gavpb45, PJT-148702 Natural Sciences and Engineering Research Council, RGPIN-2020-04876 Canada Research Chairs, https://ror.org/0517h6h17, #950-229792
Rxiv cytoskeleton

📰 "Histone H3 lysine methyltransferase activities control compartmentalization of human centromeres"
doi.org/doi:10.1101/2025.07.01
pubmed.ncbi.nlm.nih.gov/406312
#Microtubule

bioRxiv · Histone H3 lysine methyltransferase activities control compartmentalization of human centromeresCentromeres are essential chromosomal regions that ensure accurate genome segregation during cell division. They are organized into epigenetically discrete compartments: a Centromere Protein A (CENP-A)-rich core for microtubule attachment and surrounding heterochromatic pericentromeres that promote cohesion. Despite their importance, the mechanisms that define, enforce and partition these chromatin domains remain poorly understood. To address this, we disrupted key H3K9 methyltransferases– SUV39H1, SUV39H2, and SETDB1– that establish heterochromatin in humans. We find that SETDB1 is required for H3K9 dimethylation at core centromeres, while SUV39H1/2 complete trimethylation. Unexpectedly, depleting all three enzymes results in aberrantly high H3K9me3, driving CENP-A expansion into pericentromeres. This promiscuous deposition is mediated by G9a/GLP methyltransferases, which selectively reestablish H3K9me3 within the centromere core. SETDB1, regardless of its enzymatic activity, blocks G9a/GLP-mediated heterochromatin deposition and CENP-A expansion, revealing a novel, catalytic-independent function in safeguarding centromeres. Overall, our work defines the molecular logic governing centromeric repression, and uncovers foundational principles of epigenetic compartmentalization. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, https://ror.org/01cwqze88, R01GM074728, T32GM007790, T32GM007276 Stanford University School of Medicine, https://ror.org/011pcwc98, Dean's Postdoctoral Award
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