Design of peptide therapeutics as protein-protein interaction inhibitors to treat neurodegenerative diseases.

Peptide therapeutics are an emerging class of drugs to treat neurodegenerative diseases by inhibiting protein-protein interactions (PPIs). Nerinetide has recently emerged as a promising therapeutic for the treatment of ischemic stroke and Alzheimer's Disease (AD). The design of this potent neuroprotective agent includes a cell penetrating peptide sequence that achieves delivery into neurons and a protein-protein inhibitory sequence that achieves inhibition of protein complex formation through mimicry.

Immunoinformatic of novel self-amplifying mRNA vaccine lipid nanoparticle against SARS-CoV-2.

We developed innovative self-amplifying mRNA (sa-mRNA) vaccine based on the derivative of S and Nsp3 proteins, which are considered crucial adhering to human host cells. We performed B-cell, Major histocompatibility complex (MHC) I, and II epitope which were merged with the KK and GPGPG linker. We also incorporated 5' cap sequence, Kozak sequence, replicase sequence, 3'/5' UTR, and poly A tail within the vaccine structure.

Location of the axon initial segment assembly can be predicted from neuronal shape.

The axon initial segment (AIS) is located at the proximal axon demarcating the boundary between axonal and somatodendritic compartments. The AIS facilitates the generation of action potentials and maintenance of neuronal polarity. In this study, we show that the location of AIS assembly, as marked by Ankyrin G, corresponds to the nodal plane of the lowest-order harmonic of the Laplace-Beltrami operator solved over the neuronal shape.

Tau target identification reveals NSF-dependent effects on AMPA receptor trafficking and memory formation.

Microtubule-associated protein tau is a central factor in Alzheimer's disease and other tauopathies. However, the physiological functions of tau are unclear. Here, we used proximity-labelling proteomics to chart tau interactomes in primary neurons and mouse brains in vivo.

The Nature of Diamino Linker and Halogen Bonding Define Selectivity of Pyrrolopyrimidine-Based LIMK1 Inhibitors.

The LIM-domain kinase (LIMK) family consists of two isoforms, LIMK1 and LIMK2, which are highly homologous, making selective inhibitor development challenging. LIMK regulates dynamics of the actin cytoskeleton, thereby impacting many cellular functions including cell morphology and motility. Here, we designed and synthesised analogues of a known pyrrolopyrimidine LIMK inhibitor with moderate selectivity for LIMK1 over LIMK2 to gain insights into which features contribute to both activity and selectivity.

Overexpression of Tropomyosin Isoform Tpm3.1 Does Not Alter Synaptic Function in Hippocampal Neurons.

Tropomyosin (Tpm) has been regarded as the master regulator of actin dynamics. Tpms regulate the binding of the various proteins involved in restructuring actin. The actin cytoskeleton is the predominant cytoskeletal structure in dendritic spines.

Deletion of the Actin-Associated Tropomyosin Leads to Reduced Cell Complexity in Cultured Hippocampal Neurons-New Insights into the Role of the C-Terminal Region of Tpm3.1.

Tropomyosins (Tpms) have been described as master regulators of actin, with products shown to be involved in early developmental processes, and the isoform Tpm3.1 controlling changes in the size of neuronal growth cones and neurite growth. Here, we used primary mouse hippocampal neurons of C57/Bl6 wild type and Bl6 transgenic mice to carry out morphometric analyses in response to the absence of products, as well as to investigate the effect of C-terminal truncation on the ability of Tpm3.

Syntaxins 6 and 8 facilitate tau into secretory pathways.

Tau pathology initiates in defined brain regions and is known to spread along neuronal connections as symptoms progress in Alzheimer's disease (AD) and other tauopathies. This spread requires the release of tau from donor cells, but the underlying molecular mechanisms remained unknown. Here, we established the interactome of the C-terminal tail region of tau and identified syntaxin 8 (STX8) as a mediator of tau release from cells.

Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity.

Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer's disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis.

Quantification and Pathogenicity of Candida albicans in Denture-Wearing and Nondenture-Wearing Elderly.

Objective:  The primary purpose of this study was to evaluate and compare the microbial loads and pathogenicity traits of oral in denture-wearing (DW; = 15) and nondenture-wearing (NDW; = 15) elderly persons.

Materials And Methods:  The fungal counts of the saliva, tongue dorsa, and prosthesis-fitting surfaces of the participants were assessed using real-time polymerase chain reaction to compare the quantity and expression of selected biofilm-associated genes (, , and ).

Statistical Analysis:  The obtained data were analyzed by one-way analysis of variance, followed by Bartlett's test.

Tropomyosin Tpm3.1 Is Required to Maintain the Structure and Function of the Axon Initial Segment.

The axon initial segment (AIS) is the site of action potential initiation and serves as a cargo transport filter and diffusion barrier that helps maintain neuronal polarity. The AIS actin cytoskeleton comprises actin patches and periodic sub-membranous actin rings. We demonstrate that tropomyosin isoform Tpm3.

CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.

Decoupling the effects of hydrophilic and hydrophobic moieties at the neuron-nanofibre interface.

Peptide-based nanofibres are a versatile class of tunable materials with applications in optoelectronics, sensing and tissue engineering. However, the understanding of the nanofibre surface at the molecular level is limited. Here, a series of homologous dilysine-diphenylalnine tetrapeptides were synthesised and shown to self-assemble into water-soluble nanofibres.

Sphingosine 1-phosphate but not Fingolimod protects neurons against excitotoxic cell death by inducing neurotrophic gene expression in astrocytes.

Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through a family of five G protein-coupled receptors, S1PR1-S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) is a potent S1P receptor agonist that causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties of FTY720 in several neurodegenerative paradigms; however, neuroprotective properties of the native ligand S1P have not been established.

Sphingosine Kinase 2 Potentiates Amyloid Deposition but Protects against Hippocampal Volume Loss and Demyelination in a Mouse Model of Alzheimer's Disease.

Sphingosine 1-phosphate (S1P) is a potent vasculoprotective and neuroprotective signaling lipid, synthesized primarily by sphingosine kinase 2 (SK2) in the brain. We have reported pronounced loss of S1P and SK2 activity early in Alzheimer's disease (AD) pathogenesis, and an inverse correlation between hippocampal S1P levels and age in females, leading us to speculate that loss of S1P is a sensitizing influence for AD. Paradoxically, SK2 was reported to mediate amyloid β (Aβ) formation from amyloid precursor protein (APP) To determine whether loss of S1P sensitizes to Aβ-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APP) mice.

Developmental Expression of Mutant PFN1 in Motor Neurons Impacts Neuronal Growth and Motor Performance of Young and Adult Mice.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment and no cure. Mutations in were identified as a cause of familial ALS (fALS) in 2012. We investigated the functional impact of mutant profilin 1 expression in spinal cords during mouse development.

Tropomodulin's Actin-Binding Abilities Are Required to Modulate Dendrite Development.

There are many unanswered questions about the roles of the actin pointed end capping and actin nucleation by tropomodulins (Tmod) in regulating neural morphology. Previous studies indicate that Tmod1 and Tmod2 regulate morphology of the dendritic arbor and spines. Tmod3, which is expressed in the brain, had only a minor influence on morphology.

A Novel Microfluidic Device-Based Neurite Outgrowth Inhibition Assay Reveals the Neurite Outgrowth-Promoting Activity of Tropomyosin Tpm3.1 in Hippocampal Neurons.

Overcoming neurite inhibition is integral for restoring neuronal connectivity after CNS injury. Actin dynamics are critical for neurite growth cone formation and extension. The tropomyosin family of proteins is a regarded as master regulator of actin dynamics.

A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism.

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans.

Peptide Nanofiber Substrates for Long-Term Culturing of Primary Neurons.

The culturing of primary neurons represents a central pillar of neuroscience research. Primary neurons are derived directly from brain tissue and recapitulate key aspects of neuronal development in an in vitro setting. Unlike neural stem cells, primary neurons do not divide; thus, initial attachment of cells to a suitable substrate is critical.

Hypoxic postconditioning enhances functional recovery following endothelin-1 induced middle cerebral artery occlusion in conscious rats.

Stroke is a leading cause of death and a major contributor to neurological disability in adults. Tissue plasminogen activator is the only approved treatment. However, due to its narrow therapeutic window, <5% of patients receive treatment.

Tropomyosin isoforms have specific effects on the transcriptome of undifferentiated and differentiated B35 neuroblastoma cells.

Unlabelled: Tropomyosins, a family of actin-associated proteins, bestow actin filaments with distinct biochemical and physical properties which are important for determining cell shape and regulating many cellular processes in eukaryotic cells. Here, we used RNA-seq to investigate the effect of four tropomyosin isoforms on gene expression in undifferentiated and differentiated rat B35 neuroblastoma cells. In undifferentiated cells, overexpression of tropomyosin isoforms Tpm1.