Tubulin and Tubulin Posttranslational Modifications in Alzheimer’s Disease and Vascular Dementia

Santiago-Mujika, Estibaliz; Lüthi-Carter, Ruth; Giorgini, Flaviano; Kalaria, Raj N.; Mukaetova‐Ladinska, Elizabeta B.

doi:10.3389/fnagi.2021.730107

Cited by 12 publications

(12 citation statements)

References 162 publications

(212 reference statements)

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“…It is well-known that reduced levels of tubulin were found in patients with VaD [ 3 ]. In our study, we detected by immunofluorescence a significant decrease of b-tubulin in animals subjected to the operation compared to Sham group in both hippocampal regions.…”

Section: Resultsmentioning

confidence: 99%

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Açai Berry Mitigates Vascular Dementia-Induced Neuropathological Alterations Modulating Nrf-2/Beclin1 Pathways

Impellizzeri

D’Amico

Fusco

et al. 2022

Cells

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The second-most common cause of dementia is vascular dementia (VaD). The majority of VaD patients experience cognitive impairment, which is brought on by oxidative stress and changes in autophagic function, which ultimately result in neuronal impairment and death. In this study, we examine a novel method for reversing VaD-induced changes brought on by açai berry supplementation in a VaD mouse model. The purpose of this study was to examine the impact of açai berries on the molecular mechanisms underlying VaD in a mouse model of the disease that was created by repeated ischemia–reperfusion (IR) of the whole bilateral carotid artery. Here, we found that açai berry was able to reduce VaD-induced behavioral alteration, as well as hippocampal death, in CA1 and CA3 regions. These effects are probably due to the modulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and Beclin-1, suggesting a possible crosstalk between these molecular pathways. In conclusion, the protective effects of açai berry could be a good supplementation in the future for the management of vascular dementia.

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Section: Resultsmentioning

confidence: 99%

“…The altered expression of these proteins may result in the death of neurons. The loss of MAP2 and β-Tubulin have been strongly associated with VaD [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Açai Berry Mitigates Vascular Dementia-Induced Neuropathological Alterations Modulating Nrf-2/Beclin1 Pathways

Impellizzeri

D’Amico

Fusco

et al. 2022

Cells

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“…Many of these drugs demonstrated beneficial effects in animal models, however those tested in humans are few and include TPI-287 and NAP (Davunetide CP201), an intranasal neuropeptide (NAPVSIPQ)(NAP) (NCT01966666) ( Gozes, 2020 ). These MSAs have not reached the clinic, however, activity-dependent neuroprotective protein (ADNP), derived from NAP, remains a potential hope and is scheduled for future clinical trials ( Varidaki et al., 2018 ; Al-Horani and Kar, 2020 ; Santiago-Mujika et al., 2021 ). A recent addition to MSAs, sabizabulin, is currently in clinical trials as an antiviral drug, suggesting possible benefit in tauopathies (NCT04388826) ( Malebari et al., 2021 ).…”

Section: Treatment Strategies For Pathological Cell-cell Fusionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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“…Finally, after 14 days of neuronal differentiation, polyglutamylation is more prevalent than acetylation in hNSC-derived neurons. This finding is contextualized by the increased levels of tubulin polyglutamylation that are seen in neurodegeneration, which increases in prevalence in proportion to age (Zempel et al, 2013;Vu et al, 2017;Santiago-Mujika et al, 2021;Bodakuntla et al, 2021). A putative role for polyglutamylated tubulin in neurodegenerative disorders is through the regulation of endoplasmic reticulum morphology (Zheng et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, while acetylation and polyglutamylation both occur in cultured rat Schwann cells, polyglutamylation is more prevalent in these glial cells (Gadau, 2015). Astrocytic PTMs of tubulin play a putative role in regulation of the Na + / K + ATPase, neurodegeneration, and the inflammatory response (Casale, Previtali & Barra, 2003; Yoshiyama et al, 2003; Youn et al, 2015; Santiago-Mujika et al, 2021). The distinct posttranslational modification profile of tubulin within the nervous system is presumed to contribute to protein function, although a detailed characterization of these relationships is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Post-Translational Tubulin Modifications in Differentiated Human Neural Stem Cells

Knight

Jogalekar

Serrano

2022

Preprint

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The tubulin protein fulfills a variety of cellular functions that range from chromosomal separation to locomotion. The functional diversity of tubulin is achieved through the expression of specific tubulin isotypes in different cell types or developmental time periods. Post-translational modifications (PTMs) of tubulin also are vital for specific intracellular tasks, such as binding and recruiting motor proteins. In neurons, the isotypic expression profile for tubulin is well characterized, and the importance of PTMs for proper neuronal function has gained recent attention due to their implication in neurodegenerative disorders. In contrast, the role of tubulin specializations in the specification of neural cell fate has received minimal attention and studies of tubulin PTMs and isotypes in neuroglia such as astrocytes are relatively few. To bridge this knowledge gap, we undertook an analysis of PTMs in neurons and astrocytes derived from the federally approved H9 hESC-derived human neural stem cell (hNSC) line. In hNSCs, basal cells can be directed to assume neural fate as neurons or astrocytes by specifying different media growth conditions. Immunocytochemical methods, fluorescent antibody probes, and confocal microscopy facilitated image acquisition of fluorescent signals from class III β- tubulin (βIII-tubulin), acetylated tubulin, and polyglutamylated tubulin. Fluorescent probe intensities were assessed with the EBImage package for the statistical programming language R and compared using Student's t-tests. Qualitative analysis indicated that βIII-tubulin, acetylated tubulin, and polyglutamylated tubulin were expressed to some degree in basal hNSCs and their media-differentiated hNSC neuronal and astroglial progeny. In media-differentiated hNSC astrocyte progeny, quantification and statistical analysis of fluorescence probe intensity showed that acetylated tubulin/ βIII-tubulin ratios were greater than the ratio for polyglutamylated tubulin/ βIII-tubulin. These findings represent a snapshot of the dynamic and varied changes tubulin expression profile during the specification of neural cell fate. Results imply that investigations of tubulin PTMs have the potential to advance our understanding of the generation and regeneration of nervous tissue.

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Tubulin and Tubulin Posttranslational Modifications in Alzheimer’s Disease and Vascular Dementia

Cited by 12 publications

References 162 publications

Açai Berry Mitigates Vascular Dementia-Induced Neuropathological Alterations Modulating Nrf-2/Beclin1 Pathways

Açai Berry Mitigates Vascular Dementia-Induced Neuropathological Alterations Modulating Nrf-2/Beclin1 Pathways

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Post-Translational Tubulin Modifications in Differentiated Human Neural Stem Cells

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