Tubulin and Tubulin Posttranslational Modifications in Alzheimer’s Disease and Vascular Dementia
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ABSTRACT:
SUBMITTER: Santiago-Mujika E
PROVIDER: S-EPMC8586541 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The microtubule (MT) cytoskeleton of a mature axon is maintained in a stabilized steady state, yet after axonal injury it can be transformed into a dynamic structure capable of supporting axon regrowth. Using Caenorhabditis elegans mechanosensory axons and in vivo imaging, we find that, in mature axons, the growth of MTs is restricted in the steady state by the depolymerizing kinesin-13 family member KLP-7. After axon injury, we observe a two-phase process of MT growth upregulation. First, the number of growing MTs increases at the injury site, concomitant with local downregulation of KLP-7. A second phase of persistent MT growth requires the cytosolic carboxypeptidase CCPP-6, which promotes ?2 modification of ?-tubulin. Both phases of MT growth are coordinated by the DLK-1 MAP kinase cascade. Our results define how the stable MT cytoskeleton of a mature neuron is converted into the dynamically growing MT cytoskeleton of a regrowing axon.
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Project description:Recent advances in mass spectrometry (MS)-based proteomics have greatly facilitated the robust identification and quantification of posttranslational modifications (PTMs), including those that are present at substoichiometric site occupancies. The abnormal posttranslational modification and accumulation of the microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD), and it is thought that the primary mode of regulation of tau occurs through PTMs. Several studies have been published regarding tau phosphorylation; however, other tau PTMs such as ubiquitylation, acetylation, methylation, oxidation, sumoylation, nitration, and glycosylation have not been analyzed as extensively. The comprehensive detection and delineation of these PTMs is critical for drug target discovery and validation. Lysine-directed PTMs including ubiquitylation, acetylation, and methylation play key regulatory roles with respect to the rates of tau turnover and aggregation. MS-based analytical approaches have been used to gain insight into the tau lysine-directed PTM signature that is most closely associated with neurofibrillary lesion formation. This chapter provides details pertaining to the liquid chromatography tandem mass spectrometry (LC-MS/MS)-based analysis of the lysine-directed posttranslational modification of tau.
| S-EPMC5220582 | biostudies-literature
Project description:The five tubulin-binding cofactors (TBC) are involved in tubulin synthesis and the formation of microtubules. Their importance is highlighted by various diseases and syndromes caused by dysfunction or mutation of these proteins. Posttranslational modifications (PTMs) of tubulin promote different characteristics, including stability-creating subpopulations of tubulin. Cell- and time-specific distribution of PTMs has only been investigated in the organ of Corti in gerbils. The aim of the presented study was to investigate the cell type-specific and time-specific expression patterns of TBC proteins and PTMs for the first time in murine cochleae over several developmental stages. For this, murine cochleae were investigated at the postnatal (P) age P1, P7 and P14 by immunofluorescence analysis. The investigations revealed several profound interspecies differences in the distribution of PTMs between gerbil and mouse. Furthermore, this is the first study to describe the spatio-temporal distribution of TBCs in any tissue ever showing a volatile pattern of expression. The expression analysis of TBC proteins and PTMs of tubulin reveals that these proteins play a role in the physiological development of the cochlea and might be essential for hearing.
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Project description:In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neuro-degenerative diseases collectively called tauopathies and which includes Alz-heimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphory-lated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterol-ogous gene expression. Here, we present an overview on common modifica-tions as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.
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Project description:Polarized transport by microtubule-based motors is critical for neuronal development and function. Selective translocation of the Kinesin-1 motor domain is the earliest known marker of axonal identity, occurring before morphological differentiation. Thus, Kinesin-1-mediated transport may contribute to axonal specification. We tested whether posttranslational modifications of tubulin influence the ability of Kinesin-1 motors to distinguish microtubule tracks during neuronal development. We detected no difference in microtubule stability between axons and minor neurites in polarized stage 3 hippocampal neurons. In contrast, microtubule modifications were enriched in a subset of neurites in unpolarized stage 2 cells and the developing axon in polarized stage 3 cells. This enrichment correlated with the selective accumulation of constitutively active Kinesin-1 motors. Increasing tubulin acetylation, without altering the levels of other tubulin modifications, did not alter the selectivity of Kinesin-1 accumulation in polarized cells. However, globally enhancing tubulin acetylation, detyrosination, and polyglutamylation by Taxol treatment or inhibition of glycogen synthase kinase 3beta decreased the selectivity of Kinesin-1 translocation and led to the formation of multiple axons. Although microtubule acetylation enhances the motility of Kinesin-1, the preferential translocation of Kinesin-1 on axonal microtubules in polarized neuronal cells is not determined by acetylation alone but is probably specified by a combination of tubulin modifications.
| S-EPMC2820422 | biostudies-literature
Project description:There are many subtypes of dementia without any minimally invasive, low-cost and efficient diagnostic biomarkers. MicroRNA (miRNA) are easily gained and accessible from patients, which may be a promising biomarker for dementia diagnosis and differential diagnosis. We make a completely expression analysis of serum miRNA from 24 participants including post-stroke cognitive impairment (PSCI) group (n=6), post-stroke non-cognitive impairment (PSCI) group, Alzheimer's Disease (AD) group (n=6) and normal control group (NC) group (n=6). Different expression miRNA (DE -miRNA) were screened by LIMMA ebayes method, Benjamini-Hochberg check and fold change (P < 0.05, |log2FC|≥1), we construct a DE-miRNA-key gene-signaling pathway network, the roles of DE-miRNA and related genes and signaling pathways in AD and PSCI were deduced through comprehensive network construction and literature search.
2024-04-17 | GSE218605 | GEO
Project description:BACKGROUND: Novel biomarkers are important for identifying as well as differentiating subcortical vascular dementia (SVD) and Alzheimer's disease (AD) at an early stage in the disease process. METHODS: In two independent cohorts, a multiplex immunoassay was utilized to analyze 90 proteins in cerebrospinal fluid (CSF) samples from dementia patients and patients at risk of developing dementia (mild cognitive impairment). RESULTS: The levels of several CSF proteins were increased in SVD and its incipient state, and in moderate-to-severe AD compared with the control group. In contrast, some CSF proteins were altered in AD, but not in SVD. The levels of heart-type fatty acid binding protein (H-FABP) were consistently increased in all groups with dementia but only in some of their incipient states. CONCLUSIONS: In summary, these results support the notion that SVD and AD are driven by different pathophysiological mechanisms reflected in the CSF protein profile and that H-FABP in CSF is a general marker of neurodegeneration.
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Project description:IntroductionMedin, an aging-associated amyloidogenic protein, induces cerebrovascular dysfunction and inflammation. We investigated the relationship between cerebrovascular medin and Alzheimer's disease (AD) and vascular dementia (VaD).MethodsCerebral arteriole medin was quantified from 91 brain donors with no dementia (ND), AD, VaD, or combined AD and VaD. Correlation analyses evaluated the relationship between arteriole medin, and plaques, tangles, or white matter lesions (WML). Receiver operating characteristic and regression analyses assessed whether medin is predictive of AD or VaD versus other cerebrovascular pathologies (circle of Willis [CoW] atherosclerosis and cerebral amyloid angiopathy [CAA]).ResultsArteriole medin was higher in those with AD, VaD, or combined AD/VaD versus ND (P < .05), and correlated with tangle, plaque, and WML, but not CAA or CoW atherosclerosis. Among cerebrovascular pathologies, medin was the strongest predictor of AD diagnosis, whereas CoW atherosclerosis and arteriole medin were predictors of VaD.DiscussionCerebral arteriole medin is associated with and could be a potential novel risk factor or biomarker for AD and VaD.
| S-EPMC7447901 | biostudies-literature
Project description:This study examines whether neuroticism is differentially associated with risk of incident Alzheimer's disease (AD), vascular dementia (VD), and frontotemporal dementia (FTD) using a prospective study design. Participants from the UK Biobank (N = 401,422) completed a self-report neuroticism scale in 2006-2010 and incident all-cause dementia, AD, VD, and FTD were ascertained using electronic health records or death records up to 2018. During an average follow-up of 8.8 years (3,566,123 person-years), there were 1798 incident of all-cause dementia, 675 AD, 376 VD, and 81 FTD. Accounting for age and sex, compared to individuals in the low quartile, individuals in the top quartile of neuroticism had higher risk of all-cause dementia (HR = 1.70; 95% CI: 1.49-1.93), AD (HR = 1.42; 1.15-1.75), VD (HR = 1.73; 1.30-2.29), but not FTD (HR = 0.89; 0.49-1.63). The associations with AD and VD were attenuated but remained significant after further accounting for education, household income, deprivation index, diabetes, hypertension, stroke, heart attack, ever smoker, physical activity, obesity, hemoglobin A1c, C-reactive protein, and low-density lipoprotein. The associations were not moderated by socioeconomic status. The findings were consistent in analyses that excluded cases that occurred within the first 5 years of follow-up. In conclusion, neuroticism is a robust predictor of incident AD and VD, but not FTD. This pattern suggests that the affective symptoms that distinguish dementia types may partly reflect premorbid differences in trait neuroticism.
| S-EPMC8192471 | biostudies-literature
Project description:ObjectivesThe association between gout and dementia, Alzheimer's disease (AD), or vascular dementia (VD) is not fully understood. The aim of this meta-analysis was to evaluate the risk of all-cause dementia, AD, and VD in gout patients with or without medication.MethodsData sources were PubMed, Embase, the Cochrane Library, and reference lists of included studies. This meta-analysis included cohort studies assessing whether the risk of all-cause dementia, AD, and VD was associated with gout. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to access the overall certainty of evidence. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a random-effects model, and publication bias was assessed with funnel plots and Egger's test.ResultsA total of six cohort studies involving 2,349,605 individuals were included in this meta-analysis, which were published between 2015 and 2022. The pooling analysis shows that the risk of all-cause dementia was decreased in gout patients [RR = 0.67, 95% CI (0.51, 0.89), I2 = 99%, P = 0.005, very low quality], especially in gout patients with medication [RR = 0.50, 95% CI (0.31, 0.79), I2 = 93%, P = 0.003, low quality]. The risk of AD [RR = 0.70, 95% CI (0.63, 0.79), I2 = 57.2%, P = 0.000, very low quality] and VD [RR = 0.68, 95% CI (0.49, 0.95), I2 = 91.2%, P = 0.025, very low quality] was also decreased in gout patients. Despite the large heterogeneity, the sensitivity analysis indicated that the results were robust, and there was little evidence of publication bias.ConclusionThe risk of all-cause dementia, AD, and VD is decreased in gout patients, but the quality of evidence is generally low. More studies are still needed to validate and explore the mechanisms of this association.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails, identifier: CRD42022353312.
| S-EPMC10169719 | biostudies-literature