Microtubule dynamics in cytoskeleton, neurodegenerative and psychiatric disease

Microtubules (MTs) are fundamental polymers composed by α and β tubulin, they provide integrity to neuronal cell and are necessaries in intracellular trafficking and organization. The extension and retraction of MTs occur with the addition or removal of α and β tubulin subunits and the binding with microtubule associated proteins (MAPs) that selectively target specific tubulin regions, manipulating the MT dynamics and function. Altered MT homeostasis can compromise the function of MTs in the structural integrity and axonal transport inside the neuron. Here I review the evidence of MT anomalies in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and traumatic brain injury and psychiatric disorders, such as depression, schizophrenia, and bipolar disorder. The focus of this review is to point out which can be the impact of MT issues in the major neurodegenerative diseases and discuss which MT abnormalities can lead to psychiatric illnesses.

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Codon harmonization reduces amino acid misincorporation in bacterially expressed P. falciparum proteins and improves their immunogenicity

AMB Express ◽

10.1186/s13568-019-0890-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Neeraja Punde ◽

Jennifer Kooken ◽

Dagmar Leary ◽

Patricia M. Legler ◽

Evelina Angov

Keyword(s):

Protein Structure ◽

Amino Acid ◽

Codon Usage ◽

Dna Sequences ◽

Structural Integrity ◽

Host Cells ◽

Loss Of Function ◽

Species Specific ◽

And Function ◽

The Impact

Abstract Codon usage frequency influences protein structure and function. The frequency with which codons are used potentially impacts primary, secondary and tertiary protein structure. Poor expression, loss of function, insolubility, or truncation can result from species-specific differences in codon usage. “Codon harmonization” more closely aligns native codon usage frequencies with those of the expression host particularly within putative inter-domain segments where slower rates of translation may play a role in protein folding. Heterologous expression of Plasmodium falciparum genes in Escherichia coli has been a challenge due to their AT-rich codon bias and the highly repetitive DNA sequences. Here, codon harmonization was applied to the malarial antigen, CelTOS (Cell-traversal protein for ookinetes and sporozoites). CelTOS is a highly conserved P. falciparum protein involved in cellular traversal through mosquito and vertebrate host cells. It reversibly refolds after thermal denaturation making it a desirable malarial vaccine candidate. Protein expressed in E. coli from a codon harmonized sequence of P. falciparum CelTOS (CH-PfCelTOS) was compared with protein expressed from the native codon sequence (N-PfCelTOS) to assess the impact of codon usage on protein expression levels, solubility, yield, stability, structural integrity, recognition with CelTOS-specific mAbs and immunogenicity in mice. While the translated proteins were expected to be identical, the translated products produced from the codon-harmonized sequence differed in helical content and showed a smaller distribution of polypeptides in mass spectra indicating lower heterogeneity of the codon harmonized version and fewer amino acid misincorporations. Substitutions of hydrophobic-to-hydrophobic amino acid were observed more commonly than any other. CH-PfCelTOS induced significantly higher antibody levels compared with N-PfCelTOS; however, no significant differences in either IFN-γ or IL-4 cellular responses were detected between the two antigens.

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Regulatory Roles of Bone in Neurodegenerative Diseases

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.610581 ◽

2020 ◽

Vol 12 ◽

Author(s):

Zhengran Yu ◽

Zemin Ling ◽

Lin Lu ◽

Jin Zhao ◽

Xiang Chen ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

The Elderly ◽

Lymphoid Organ ◽

The Body ◽

Hematopoietic Stem ◽

Brain Functions ◽

And Function ◽

The Impact ◽

The Brain

Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.

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The structured core of human β tubulin confers isotype-specific polymerization properties

The Journal of Cell Biology ◽

10.1083/jcb.201603050 ◽

2016 ◽

Vol 213 (4) ◽

pp. 425-433 ◽

Cited By ~ 52

Author(s):

Melissa C. Pamula ◽

Shih-Chieh Ti ◽

Tarun M. Kapoor

Keyword(s):

Dynamic Instability ◽

Sequence Divergence ◽

Regulatory Proteins ◽

Microtubule Dynamic ◽

Microtubule Associated Proteins ◽

Cytoskeleton Organization ◽

Wide Range ◽

Associated Proteins ◽

And Function ◽

Β Tubulin

Diversity in cytoskeleton organization and function may be achieved through variations in primary sequence of tubulin isotypes. Recently, isotype functional diversity has been linked to a “tubulin code” in which the C-terminal tail, a region of substantial sequence divergence between isotypes, specifies interactions with microtubule-associated proteins. However, it is not known whether residue changes in this region alter microtubule dynamic instability. Here, we examine recombinant tubulin with human β isotype IIB and characterize polymerization dynamics. Microtubules with βIIB have catastrophe frequencies approximately threefold lower than those with isotype βIII, a suppression similar to that achieved by regulatory proteins. Further, we generate chimeric β tubulins with native tail sequences swapped between isotypes. These chimeras have catastrophe frequencies similar to that of the corresponding full-length construct with the same core sequence. Together, our data indicate that residue changes within the conserved β tubulin core are largely responsible for the observed isotype-specific changes in dynamic instability parameters and tune tubulin’s polymerization properties across a wide range.

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Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/6565396 ◽

2020 ◽

Vol 2020 ◽

pp. 1-30 ◽

Cited By ~ 6

Author(s):

Nur Shafika Mohd Sairazi ◽

K. N. S. Sirajudeen

Keyword(s):

Cell Death ◽

Natural Products ◽

Neurodegenerative Diseases ◽

Bioactive Compounds ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Neuronal Structure ◽

And Function

In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.

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The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

Cells ◽

10.3390/cells10071593 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1593

Author(s):

Nicole A. Muench ◽

Sonia Patel ◽

Margaret E. Maes ◽

Ryan J. Donahue ◽

Akihiro Ikeda ◽

...

Keyword(s):

Optic Nerve ◽

Pressure Gradient ◽

Ganglion Cells ◽

Mitochondrial Dynamics ◽

Metabolic Stress ◽

Neuronal Cell ◽

Retinal Ganglion ◽

Support Functions ◽

Dynamics And Function ◽

And Function

The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs.

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Mutational and structural study of RipA, a key enzyme inMycobacterium tuberculosiscell division: evidence for theL-to-Dinversion of configuration of the catalytic cysteine

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s1399004714013674 ◽

2014 ◽

Vol 70 (9) ◽

pp. 2295-2300 ◽

Cited By ~ 12

Author(s):

Flavia Squeglia ◽

Alessia Ruggiero ◽

Maria Romano ◽

Luigi Vitagliano ◽

Rita Berisio

Keyword(s):

Structural Integrity ◽

Cysteine Proteases ◽

Enzyme Inactivation ◽

Side Chain ◽

Catalytic Cysteine ◽

Key Enzyme ◽

And Function ◽

The Impact ◽

Daughter Cell Separation

RipA is a key cysteine protease ofMycobacterium tuberculosisas it is responsible for bacterial daughter-cell separation. Although it is an important target for antimicrobial development, its mechanism of action and its interaction pattern with its substrate are hitherto unknown. By combining crystallographic and mutational studies with functional assays and molecular modelling, it is shown that the catalytic activity of the enzyme relies on a Cys–His–Glu triad and the impact of the mutation of each residue of the triad on the structure and function of RipA is analysed. Unexpectedly, the crystallographic analyses reveal that mutation of the glutamic acid to alanine results in inversion of the configuration of the catalytic cysteine. The consequent burial of the catalytic cysteine side chain explains the enzyme inactivation upon mutation. These data point to a novel role of the acidic residue often present in the triad of cysteine proteases as a supervisor of cysteine configuration through preservation of the local structural integrity.

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A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

Scientific Reports ◽

10.1038/s41598-021-02715-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samia Sultana Lira ◽

Ishtiaque Ahammad

Keyword(s):

Neuronal Cell ◽

Surface Protein ◽

Dynamics Simulation ◽

Atomic Interaction ◽

Nucleotide Polymorphisms ◽

Ligand Complex ◽

Depth Analysis ◽

Dopamine Signaling ◽

And Function ◽

The Impact

AbstractDRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein–ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

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Impact of Chaperone-Mediated Autophagy in Brain Aging: Neurodegenerative Diseases and Glioblastoma

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.630743 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jaione Auzmendi-Iriarte ◽

Ander Matheu

Keyword(s):

Neurodegenerative Diseases ◽

Brain Aging ◽

Current Knowledge ◽

Tissue Integrity ◽

Cargo Protein ◽

Cellular Energetics ◽

The Individual ◽

And Function ◽

The Impact ◽

Chaperone Mediated Autophagy

Brain aging is characterized by a time-dependent decline of tissue integrity and function, and it is a major risk for neurodegenerative diseases and brain cancer. Chaperone-mediated autophagy (CMA) is a selective form of autophagy specialized in protein degradation, which is based on the individual translocation of a cargo protein through the lysosomal membrane. Regulation of processes such as proteostasis, cellular energetics, or immune system activity has been associated with CMA, indicating its pivotal role in tissue homeostasis. Since first studies associating Parkinson’s disease (PD) to CMA dysfunction, increasing evidence points out that CMA is altered in both physiological and pathological brain aging. In this review article, we summarize the current knowledge regarding the impact of CMA during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults.

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Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury

Cells ◽

10.3390/cells10123460 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3460

Author(s):

Larry N. Singh ◽

Shih-Han Kao ◽

Douglas C. Wallace

Keyword(s):

Mitochondrial Dna ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Genetic Factors ◽

Mitochondrial Genetics ◽

Dna Variation ◽

Parkinson’S Diseases ◽

And Function ◽

The Impact

Neurodegenerative disorders that are triggered by injury typically have variable and unpredictable outcomes due to the complex and multifactorial cascade of events following the injury and during recovery. Hence, several factors beyond the initial injury likely contribute to the disease progression and pathology, and among these are genetic factors. Genetics is a recognized factor in determining the outcome of common neurodegenerative diseases. The role of mitochondrial genetics and function in traditional neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, is well-established. Much less is known about mitochondrial genetics, however, regarding neurodegenerative diseases that result from injuries such as traumatic brain injury and ischaemic stroke. We discuss the potential role of mitochondrial DNA genetics in the progression and outcome of injury-related neurodegenerative diseases. We present a guide for understanding mitochondrial genetic variation, along with the nuances of quantifying mitochondrial DNA variation. Evidence supporting a role for mitochondrial DNA as a risk factor for neurodegenerative disease is also reviewed and examined. Further research into the impact of mitochondrial DNA on neurodegenerative disease resulting from injury will likely offer key insights into the genetic factors that determine the outcome of these diseases together with potential targets for treatment.

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The Impact of Bacteriocenoses on Sperm Vitality, Immunological and Oxidative Characteristics of Ram Ejaculates: Does the Breed Play a Role?

Animals ◽

10.3390/ani12010054 ◽

2021 ◽

Vol 12 (1) ◽

pp. 54

Author(s):

Eva Tvrdá ◽

Miroslava Kačániová ◽

Andrej Baláži ◽

Jaromír Vašíček ◽

Jakub Vozaf ◽

...

Keyword(s):

Structural Integrity ◽

Semen Quality ◽

Pearson Correlation ◽

Interleukin 1 ◽

Bacterial Load ◽

Membrane Integrity ◽

Ros Generation ◽

Male Gametes ◽

And Function ◽

The Impact

Bacterial contamination of semen is an often overlooked, yet important, factor contributing to decreased sperm vitality. Understanding the impact of bacterial presence on sperm structural integrity and functional activity may assist the development of effective strategies to prevent, or manage, bacteriospermia in the breeding practice. The aim of this study was to describe the bacterial profiles of ram semen (n = 35), and we also focused on the associations between bacteriospermia, sperm structure, and function, as well as oxidative and inflammatory characteristics of semen. For a better insight, the samples were divided into three groups, according to the breeds used in the study: native Wallachian (NW), improved Wallachian (IW), and Slovak dairy (SD) breeds. The results showed a significantly lower motility and membrane integrity in the NW group in comparison to the IW and SD groups, which was accompanied by a significantly higher concentration of leukocytes, increased reactive oxygen species (ROS) generation, and subsequent oxidative insults to the sperm lipids and proteins. Accordingly, the NW group presented with the highest bacterial load, in which Staphylococcus and Escherichia were the predominant representatives. The Pearson correlation analysis uncovered positive relationships amongst the bacterial load and leukocytospermia (r = 0.613), the extent of lipid peroxidation (r = 0.598), protein oxidation (r = 0.514), and DNA fragmentation (r = 0.638). Furthermore, positive correlations were found between the bacterial load and pro-inflammatory molecules, such as the C-reactive protein (r = 0.592), interleukin 1 (r = 0.709), and interleukin 6 (r = 0.474), indicating a possible involvement of the immune response in the process of bacteriospermia. Overall, our data indicate that ram semen quality may be equally affected by the bacterial load and diversity. Furthermore, we can assume that the presence of bacteria in ejaculates triggers inflammatory processes, causes ROS overproduction, and, thereby, contributes to alterations in the sperm structure, while at the same time compromising the fertilization ability of male gametes.

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