scholarly journals Racemization in Post-Translational Modifications Relevance to Protein Aging, Aggregation and Neurodegeneration: Tip of the Iceberg

Symmetry ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 455
Author(s):  
Victor V. Dyakin ◽  
Thomas M. Wisniewski ◽  
Abel Lajtha
Keyword(s):  
Phase Transition ◽  
Amino Acids ◽  
Energy Barrier ◽  
Protein Misfolding ◽  
Critical Factor ◽  
Living Organism ◽  
Extracellular Proteins ◽  
Thermodynamic Consideration ◽  
Age Related ◽  
And Function

Homochirality of DNA and prevalent chirality of free and protein-bound amino acids in a living organism represents the challenge for modern biochemistry and neuroscience. The idea of an association between age-related disease, neurodegeneration, and racemization originated from the studies of fossils and cataract disease. Under the pressure of new results, this concept has a broader significance linking protein folding, aggregation, and disfunction to an organism’s cognitive and behavioral functions. The integrity of cognitive function is provided by a delicate balance between the evolutionarily imposed molecular homo-chirality and the epigenetic/developmental impact of spontaneous and enzymatic racemization. The chirality of amino acids is the crucial player in the modulation the structure and function of proteins, lipids, and DNA. The collapse of homochirality by racemization is the result of the conformational phase transition. The racemization of protein-bound amino acids (spontaneous and enzymatic) occurs through thermal activation over the energy barrier or by the tunnel transfer effect under the energy barrier. The phase transition is achieved through the intermediate state, where the chirality of alpha carbon vanished. From a thermodynamic consideration, the system in the homo-chiral (single enantiomeric) state is characterized by a decreased level of entropy. The oscillating protein chirality is suggesting its distinct significance in the neurotransmission and flow of perceptual information, adaptive associative learning, and cognitive laterality. The common pathological hallmarks of neurodegenerative disorders include protein misfolding, aging, and the deposition of protease-resistant protein aggregates. Each of the landmarks is influenced by racemization. The brain region, cell type, and age-dependent racemization critically influence the functions of many intracellular, membrane-bound, and extracellular proteins including amyloid precursor protein (APP), TAU, PrP, Huntingtin, α-synuclein, myelin basic protein (MBP), and collagen. The amyloid cascade hypothesis in Alzheimer’s disease (AD) coexists with the failure of amyloid beta (Aβ) targeting drug therapy. According to our view, racemization should be considered as a critical factor of protein conformation with the potential for inducing order, disorder, misfolding, aggregation, toxicity, and malfunctions.

scholarly journals VEGF signaling regulates the fate of obstructed capillaries in mouse cortex

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Patrick Reeson ◽  
Kevin Choi ◽  
Craig E Brown
Keyword(s):  
Critical Factor ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Vegf Signaling ◽  
Capillary Rarefaction ◽  
Age Related ◽  
Mouse Cortex ◽  
Cortical Capillaries ◽  
And Function

Cortical capillaries are prone to obstruction, which over time, could have a major impact on brain angioarchitecture and function. The mechanisms that govern the removal of these obstructions and what long-term fate awaits obstructed capillaries, remains a mystery. We estimate that ~0.12% of mouse cortical capillaries are obstructed each day (lasting >20 min), preferentially in superficial layers and lower order branches. Tracking natural or microsphere-induced obstructions revealed that 75–80% of capillaries recanalized within 24 hr. Remarkably, 30% of all obstructed capillaries were pruned by 21 days, including some that had regained flow. Pruning involved regression of endothelial cells, which was not compensated for by sprouting. Using this information, we predicted capillary loss with aging that closely matched experimental estimates. Genetic knockdown or inhibition of VEGF-R2 signaling was a critical factor in promoting capillary recanalization and minimizing subsequent pruning. Our studies reveal the incidence, mechanism and long-term outcome of capillary obstructions which can also explain age-related capillary rarefaction.

scholarly journals Isomerization of Asp is essential for assembly of amyloid-like fibrils of αA-crystallin-derived peptide

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250277
Author(s):  
Kosuke Magami ◽  
Naomi Hachiya ◽  
Kazuo Morikawa ◽  
Noriko Fujii ◽  
Takumi Takata
Keyword(s):  
Protein Misfolding ◽  
Structure And Function ◽  
Thioflavin T ◽  
Human Lens ◽  
Post Translational Modifications ◽  
Age Related ◽  
And Function ◽  
Β Sheet ◽  
Aspartate Residue ◽  
Positively Charged

Post-translational modifications are often detected in age-related diseases associated with protein misfolding such as cataracts from aged lenses. One of the major post-translational modifications is the isomerization of aspartate residues (L-isoAsp), which could be non-enzymatically and spontaneously occurring in proteins, resulting in various effects on the structure and function of proteins including short peptides. We have reported that the structure and function of an αA66–80 peptide, corresponding to the 66–80 (66SDRDKFVIFLDVKHF80) fragment of human lens αA-crystallin, was dramatically altered by the isomerization of aspartate residue (Asp) at position 76. In the current study, we observed amyloid-like fibrils of L-isoAsp containing αA66–80 using electron microscopy. The contribution of each amino acid for the peptide structure was further evaluated by circular dichroism (CD), bis-ANS, and thioflavin T fluorescence using 14 alanine substituents of αA66–80, including L-isoAsp at position 76. CD of 14 alanine substituents demonstrated random coiled structures except for the substituents of positively charged residues. Bis-ANS fluorescence of peptide with substitution of hydrophobic residue with alanine revealed decreased hydrophobicity of the peptide. Thioflavin T fluorescence also showed that the hydrophobicity around Asp76 of the peptide is important for the formation of amyloid-like fibrils. One of the substitutes, H79A (SDRDKFVIFL(L-isoD)VKAF) demonstrated an exact β-sheet structure in CD and highly increased Thioflavin T fluorescence. This phenomenon was inhibited by the addition of protein-L-isoaspartate O-methyltransferase (PIMT), which is an enzyme that changes L-isoAsp into Asp. These interactions were observed even after the formation of amyloid-like fibrils. Thus, isomerization of Asp in peptide is key to form fibrils of αA-crystallin-derived peptide, and L-isoAsp on fibrils can be a candidate for disassembling amyloid-like fibrils of αA-crystallin-derived peptides.

The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders

2020 ◽  
Vol 21 (9) ◽  
pp. 846-859
Author(s):  
Mohd Saeed ◽  
Mohd Adnan Kausar ◽  
Rajeev Singh ◽  
Arif J. Siddiqui ◽  
Asma Akhter
Keyword(s):  
Protein Misfolding ◽  
Covalent Binding ◽  
Critical Role ◽  
Enzymatic Reaction ◽  
Treatment Strategies ◽  
Bioactive Molecules ◽  
Carbonyl Stress ◽  
Defense System ◽  
Pathological Conditions ◽  
Age Related

Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.

scholarly journals Association of Human Plasma Metabolomics with Delayed Dark Adaptation in Age-Related Macular Degeneration

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 183
Author(s):  
Kevin M Mendez ◽  
Janice Kim ◽  
Inês Laíns ◽  
Archana Nigalye ◽  
Raviv Katz ◽  
...  
Keyword(s):  
Amino Acids ◽  
Fatty Acid ◽  
Macular Degeneration ◽  
Dark Adaptation ◽  
Ultra Performance Liquid Chromatography ◽  
Cross Sectional Study ◽  
Age Related Macular Degeneration ◽  
Cross Sectional ◽  
Age Related ◽  
Vitreoretinal Disease

The purpose of this study was to analyze the association between plasma metabolite levels and dark adaptation (DA) in age-related macular degeneration (AMD). This was a cross-sectional study including patients with AMD (early, intermediate, and late) and control subjects older than 50 years without any vitreoretinal disease. Fasting blood samples were collected and used for metabolomic profiling with ultra-performance liquid chromatography–mass spectrometry (LC-MS). Patients were also tested with the AdaptDx (MacuLogix, Middletown, PA, USA) DA extended protocol (20 min). Two measures of dark adaptation were calculated and used: rod-intercept time (RIT) and area under the dark adaptation curve (AUDAC). Associations between dark adaption and metabolite levels were tested using multilevel mixed-effects linear modelling, adjusting for age, gender, body mass index (BMI), smoking, race, AMD stage, and Age-Related Eye Disease Study (AREDS) formulation supplementation. We included a total of 71 subjects: 53 with AMD (13 early AMD, 31 intermediate AMD, and 9 late AMD) and 18 controls. Our results revealed that fatty acid-related lipids and amino acids related to glutamate and leucine, isoleucine and valine metabolism were associated with RIT (p < 0.01). Similar results were found when AUDAC was used as the outcome. Fatty acid-related lipids and amino acids are associated with DA, thus suggesting that oxidative stress and mitochondrial dysfunction likely play a role in AMD and visual impairment in this condition.

scholarly journals Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiya Börsch ◽  
Daniel J. Ham ◽  
Nitish Mittal ◽  
Lionel A. Tintignac ◽  
Eugenia Migliavacca ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Inflammatory Responses ◽  
Molecular Data ◽  
Model Organisms ◽  
Sequencing Data ◽  
Phenotypic Analysis ◽  
Age Related ◽  
Analogous Data ◽  
Species Specific ◽  
And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

The Association Between Sarcopenia and Postoperative Outcomes Among Older Adults With Hip Fracture: A Systematic Review

2021 ◽  
pp. 073346482110065
Author(s):  
Ming-Hsiu Chiang ◽  
Yi-Jie Kuo ◽  
Yu-Pin Chen
Keyword(s):  
Systematic Review ◽  
Older Adults ◽  
Hip Fracture ◽  
Postoperative Mortality ◽  
Clinical Event ◽  
High Morbidity ◽  
Adverse Health Outcomes ◽  
Age Related ◽  
Study Selection ◽  
And Function

Hip fracture is a serious clinical event with high morbidity and mortality. Sarcopenia is characterized by age-related loss of muscle mass and function, leading to several adverse health outcomes. In this systematic review, no limitation criteria were used for study selection and 327 studies were identified in the initial search. Of these, 11 studies comprising a total of 2,314 patients were selected. The overall proportion of older adults with hip fracture having sarcopenia was 44%, with a disparity of approximately 10% between men and women. Most studies have indicated that older adults with sarcopenia had poorer postoperative functional recovery than those without sarcopenia; the association between sarcopenia and high postoperative mortality or long hospital stay was heterogeneous. Well-organized studies with longer follow-up periods are warranted.

Gill microbiome structure and function in the chemosymbiotic coastal lucinid Stewartia floridana

2021 ◽  
Author(s):  
Shen Jean Lim ◽  
Brenton Davis ◽  
Danielle Gill ◽  
John Swetenburg ◽  
Laurie C Anderson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Nutrient Cycling ◽  
Bacterial Communities ◽  
Structure And Function ◽  
Differentially Expressed ◽  
Seagrass Species ◽  
Bare Sand ◽  
And Function

Abstract Lucinid bivalves harbor environmentally acquired, chemosynthetic, gammaproteobacterial gill endosymbionts. Lucinid gill microbiomes, which may contain other gammaproteobacterial and/or spirochete taxa, remain under-sampled. To understand inter-host variability of the lucinid gill microbiome, specifically in the bacterial communities, we analyzed the microbiome content of Stewartia floridana collected from Florida. Sampled gills contained a monospecific gammaproteobacterial endosymbiont expressing lithoautotrophic, mixotrophic, diazotrophic, and C1 compound oxidation-related functions previously characterized in similar lucinid species. Another low-abundance Spirochaeta-like species in ∼72% of the sampled gills was most closely related to Spirochaeta-like species in another lucinid Phacoides pectinatus and formed a clade with known marine Spirochaeta symbionts. The spirochete expressed genes were involved in heterotrophy and the transport of sugars, amino acids, peptides, and other substrates. Few muscular and neurofilament genes from the host and none from the gammaproteobacterial and spirochete symbionts were differentially expressed among quadrats predominantly covered with seagrass species or 80% bare sand. Our results suggest that spirochetes are facultatively associated with S. floridana, with potential scavenging and nutrient cycling roles. Expressed stress- and defense-related functions in the host and symbionts also suggest species-species communications, which highlight the need for further study of the interactions among lucinid hosts, their microbiomes, and their environment.

scholarly journals Formaldehyde and De/Methylation in Age-Related Cognitive Impairment

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 913
Author(s):  
Ting Li ◽  
Yan Wei ◽  
Meihua Qu ◽  
Lixian Mou ◽  
Junye Miao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cell Proliferation ◽  
Cognitive Impairment ◽  
Metabolic Pathways ◽  
Memory Formation ◽  
Epigenetic Alterations ◽  
Diagnostic Biomarker ◽  
Reactive Substance ◽  
Age Related ◽  
Novel Therapeutic

Formaldehyde (FA) is a highly reactive substance that is ubiquitous in the environment and is usually considered as a pollutant. In the human body, FA is a product of various metabolic pathways and participates in one-carbon cycle, which provides carbon for the synthesis and modification of bio-compounds, such as DNA, RNA, and amino acids. Endogenous FA plays a role in epigenetic regulation, especially in the methylation and demethylation of DNA, histones, and RNA. Recently, epigenetic alterations associated with FA dysmetabolism have been considered as one of the important features in age-related cognitive impairment (ARCI), suggesting the potential of using FA as a diagnostic biomarker of ARCI. Notably, FA plays multifaceted roles, and, at certain concentrations, it promotes cell proliferation, enhances memory formation, and elongates life span, effects that could also be involved in the aetiology of ARCI. Further investigation of and the regulation of the epigenetics landscape may provide new insights about the aetiology of ARCI and provide novel therapeutic targets.

scholarly journals Targeting Senescent Cells to Counter Aging and Aging-Related Conditions

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 818-818
Author(s):  
Nathan LeBrasseur
Keyword(s):  
Human Populations ◽  
Geriatric Syndromes ◽  
Preclinical Models ◽  
Pharmacological Agents ◽  
New Class ◽  
Age Related ◽  
Selective Elimination ◽  
Early Phase Clinical Trials ◽  
And Function ◽  
State Of The Science

Abstract In response to various forms of age-associated damage, cells can enter a state of senescence. Senescent cells can compromise the health and function of a tissue, and their accumulation with advancing age is believed to contribute to age-related diseases and geriatric syndromes. In preclinical models (i.e., mice), selective elimination of senescent cells through either genetic approaches or a new class of pharmacological agents, termed “senolytics”, has been show to effectively delay, prevent, or reverse the onset and/or progression of pulmonary disease, osteoporosis, atherosclerosis, diabetes, cognitive decline, and several other conditions. Thus, considerable efforts are underway to optimize pharmacological strategies and test their effectiveness in human populations. This seminar will highlight the state-of-the-science of senolytic drugs, and the opportunities and challenges for early phase clinical trials in humans.

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