Due to molecular forces, biomacromolecules assemble into liquid condensates or solid aggregates, and their corresponding formation and dissolution processes are controlled. Protein homeostasis is disrupted by increasing age or environmental stress, leading to irreversible protein aggregation. Hypoxic pressure is an important factor in this process, and uncontrolled protein aggregation has been widely observed in hypoxia‑related conditions such as neurodegenerative disease, cardiovascular disease, hypoxic brain injury and cancer. Biomolecular condensates are also high‑order complexes assembled from macromolecules. Although they exist in different phase from protein aggregates, they are in dynamic balance under certain conditions, and their activation or assembly are considered as important regulatory processes in cell survival with hypoxic pressure. Therefore, a better understanding of the relationship between hypoxic stress, protein aggregation and biomolecular condensation will bring marked benefits in the clinical treatment of various diseases. The aim of the present review was to summarize the underlying mechanisms of aggregate assembly and dissolution induced by hypoxic conditions, and address recent breakthroughs in understanding the role of aggregates in hypoxic‑related diseases, given the hypotheses that hypoxia induces macromolecular assemblage changes from a liquid to a solid phase, and that adenosine triphosphate depletion and ATP‑driven inactivation of multiple protein chaperones play important roles among the process. Moreover, it is anticipated that an improved understanding of the adaptation in hypoxic environments could extend the overall survival of patients and provide new strategies for hypoxic‑related diseases.

Amyloid is defined as a fibrous quaternary structure formed by assembling protein or peptide monomers into intermolecularly hydrogen linked β-sheets. There is a prevalent issue with protein aggregation and the buildup of amyloid molecules, which results in human neurological illnesses including Alzheimer\'s and Parkinson\'s. But it is now evident that many organisms, like bacteria, fungi as well as humans, use the same fibrillar structure to carry out a variety of biological functions, such as structure and protection supporting interface transitions and cell-cell recognition, protein control and storage, epigenetic inheritance, and memory. Recent discoveries of self-assembling amyloidogenic peptides and proteins, based on the amyloid core structure, give rise to interesting biomaterials with potential uses in numerous industries. These functions dramatically diverge from the initial conception of amyloid fibrils as intrinsically diseased entities. Apart from the natural ability of amyloids to spontaneously arrange themselves and their exceptional material characteristics, this aspect has prompted extensive research into engineering artificial amyloids for generating various nanostructures, molecular substances, and combined materials. Here, we discuss significant developments in the artificial design of useful amyloids as well as how amyloid materials serve as examples of how function emerges from protein self-assembly at various length scales.

The small heat shock proteins (sHSPs), whose molecular weight ranges from 12∼43 kDa, are members of the heat shock protein (HSP) family that are widely found in all organisms. As intracellular stress resistance molecules, sHSPs play an important role in maintaining the homeostasis of the intracellular environment under various stressful conditions. A total of 10 sHSPs have been identified in mammals, sharing conserved α-crystal domains combined with variable N-terminal and C-terminal regions. Unlike large-molecular-weight HSP, sHSPs prevent substrate protein aggregation through an ATP-independent mechanism. In addition to chaperone activity, sHSPs were also shown to suppress apoptosis, ferroptosis, and senescence, promote autophagy, regulate cytoskeletal dynamics, maintain membrane stability, control the direction of cellular differentiation, modulate angiogenesis, and spermatogenesis, as well as attenuate the inflammatory response and reduce oxidative damage. Phosphorylation is the most significant post-translational modification of sHSPs and is usually an indicator of their activation. Furthermore, abnormalities in sHSPs often lead to aggregation of substrate proteins and dysfunction of client proteins, resulting in disease. This paper reviews the various biological functions of sHSPs in mammals, emphasizing the roles of different sHSPs in specific cellular activities. In addition, we discuss the effect of phosphorylation on the function of sHSPs and the association between sHSPs and disease.

Proteins are the most common biological macromolecules in living system and are building blocks of life. They are extremely dynamic in structure and functions. Due to several modifications, proteins undergo misfolding, leading to aggregation and thereby developing neurodegenerative and systemic diseases. Understanding the pathology of these diseases and the techniques used to diagnose them is therefore crucial for their effective management . There are several techniques, currently being in use to diagnose them and those will be discussed in this review.
Current review aims to discuss an overview of protein aggregation and the underlying mechanisms linked to neurodegeneration and systemic diseases. Also, the review highlights protein misfolding disorders, their clinical diagnosis, and treatment strategies.
Literature related to neurodegenerative and systemic diseases was explored through PubMed, Google Scholar, Scopus, and Medline databases. The keywords used for literature survey and analysis are protein aggregation, neurodegenerative disorders, Alzheimer\'s disease, Parkinson\'s disease, systemic diseases, protein aggregation mechanisms, etc. DISCUSSION /CONCLUSION: This review summarises the pathogenesis of neurodegenerative and systemic disorders caused by protein misfolding and aggregation. The clinical diagnosis and therapeutic strategies adopted for the management of these diseases are also discussed to aid in a better understanding of protein misfolding disorders. Many significant concerns about the role, characteristics, and consequences of protein aggregates in neurodegenerative and systemic diseases are not clearly understood to date. Regardless of technological advancements, there are still great difficulties in the management and cure of these diseases. Therefore, for better understanding, diagnosis, and treatment of neurodegenerative and systemic diseases, more studies to identify novel drugs that may aid in their treatment and management are required.

Alzheimer\'s disease (AD) is the most common form of dementia. The physiopathology of AD is well described by the presence of two neuropathological features: amyloid plaques and tau neurofibrillary tangles. In the last decade, neuroinflammation and cellular stress have gained importance as key factors in the development and pathology of AD. Chronic cellular stress occurs in degenerating neurons. Stress Granules (SGs) are nonmembranous organelles formed as a response to stress, with a protective role; however, SGs have been noted to turn into pathological and neurotoxic features when stress is chronic, and they are related to an increased tau aggregation. On the other hand, correct lipid metabolism is essential to good function of the brain; apolipoproteins are highly associated with risk of AD, and impaired cholesterol efflux and lipid transport are associated with an increased risk of AD. In this review, we provide an insight into the relationship between cellular stress, SGs, protein aggregation, and lipid metabolism in AD.

Most of the cell\'s chemical reactions and structural components are facilitated by proteins. But proteins are highly dynamic molecules, where numerous modifications or changes in the cellular environment can affect their native conformational fold leading to protein aggregation. Various stress conditions, such as oxidative stress, mutations and metal toxicity may cause protein misfolding and aggregation by shifting the conformational equilibrium towards more aggregation-prone states. Most of the protein misfolding diseases (PMDs) involve aggregation of protein. We have discussed such proteins like Aβ peptide, α-synuclein, amylin and lysozyme involved in Alzheimer\'s, Parkinson\'s, type II diabetes and non-neuropathic systemic amyloidosis respectively. Till date, all advances in PMDs therapeutics help symptomatically but do not prevent the root cause of the disease, i.e., the aggregation of protein involved in the diseases. Current efforts focused on developing therapies for PMDs have employed diverse strategies; repositioning pre-existing drugs as it saves time and money; natural compounds that are touted as potential drug candidates have an advantage of being taken in diet normally and will induce lesser side effects. This review also covers recently developed therapeutic strategies like antisense drugs and disaggregases which has yielded therapeutic agents that have transitioned from preclinical studies into human clinical trials.

Aggregation of amyloid beta into amyloid plaques in the brain is a hallmark characteristic of Alzheimer\'s disease. Therapeutics aimed at preventing or retarding amyloid formation often rely on detailed characterization of the underlying mechanism and kinetics of protein aggregation. Surface plasmon resonance (SPR) spectroscopy is a robust technique used to determine binding affinity and kinetics of biomolecular interactions. This approach has been used to characterize the mechanism of aggregation of amyloid beta but there are multiple pitfalls that need to be addressed when working with this and other amyloidogenic proteins. The choice of method for analyte preparation and ligand immobilization to a sensor chip can lead to different theoretical and practical implications in terms of the mathematical modelling of binding data, different mechanisms of binding and the presence of different interacting species. This review examines preparation methods for SPR characterisation of the aggregation of amyloid beta and their influence on the findings derived from such studies.

Huntington\'s disease (HD) is a distressing, innate neurodegenerative disease that descends from CAG repeat expansion in the huntingtin gene causing behavioral changes, motor dysfunction, and dementia in children and adults. Mutation in huntingtin (HTT) protein has been suggested to cause neuron loss in the cortex and striatum through various mechanisms, including abnormal regulation of transcription, proteasomal dysfunction, posttranslational modification, and other events regulating toxicity. Pathogenesis of HD involves cleavage of the huntingtin protein followed by the neuronal accumulation of its aggregated form. Several research groups made possible efforts to reduce huntingtin gene expression, protein accumulation, and protein aggregation using inhibitors and molecular chaperones as developing drugs against HD. Herein, we review the mechanism proposed towards the formation of HTT protein aggregation and the impact of therapeutic strategies for the treatment of HD.

Estimating the amyloid level in yeast Saccharomyces, we found out that the red pigment (product of polymerization of aminoimidazole ribotide) accumulating in ade1 and ade2 mutants leads to drop of the amyloid content. We demonstrated in vitro that fibrils of several proteins grown in the presence of the red pigment stop formation at the protofibril stage and form stable aggregates due to coalescence. Also, the red pigment inhibits reactive oxygen species accumulation in cells. This observation suggests that red pigment is involved in oxidative stress response. We developed an approach to identify the proteins whose aggregation state depends on prion (amyloid) or red pigment presence. These sets of proteins overlap and in both cases involve many different chaperones. Red pigment binds amyloids and is supposed to prevent chaperone-mediated prion propagation. An original yeast-Drosophila model was offered to estimate the red pigment effect on human proteins involved in neurodegeneration. As yeast cells are a natural feed of Drosophila, we could compare the data on transgenic flies fed on red and white yeast cells. Red pigment inhibits aggregation of human Amyloid beta and α-synuclein expressed in yeast cells. In the brain of transgenic flies, the red pigment diminishes amyloid beta level and the area of neurodegeneration. An improvement in memory and viability accompanied these changes. In transgenic flies expressing human α-synuclein, the pigment leads to a decreased death rate of dopaminergic neurons and improves mobility. The obtained results demonstrate yeast red pigment potential for the treatment of neurodegenerative diseases.

All proteins have the inherent ability to undergo transformation from their native structure to a β sheet rich fibrillar structure, called amyloid when subjected to specific conditions. Proteins with a high propensity to form amyloid fibrils have been implicated in a variety of disorders like Alzheimer\'s disease, Parkinson\'s disease, Type II diabetes, Amyotrophic Lateral Sclerosis (ALS) and prion diseases. Among the various critical factors that modulate the process of amyloid formation, disulfide bonds have been identified as one of the key determinants of amyloid propensity in proteins. Studies have shown that intra-molecular disulfide bonds impart stability to the native structure of a protein and decrease the tendency for amyloid aggregation, whereas intermolecular disulfide bonds aid in the process of aggregation. In this review, we will analyze the varying effects of both intra as well as inter-molecular disulfide bonds on the amyloid aggregation propensities of a few proteins associated with amyloid disorders.