-linked protein glycosylation in (formerly DPANN) archaea and their hosts.

Members of the kingdom , previously known as DPANN archaea, are characterized by ultrasmall cell sizes and reduced genomes. They primarily thrive through ectosymbiotic interactions with specific hosts in diverse environments. Recent successful cultivations have emphasized the importance of adhesion to host cells for understanding the ecophysiology of .

[Widely Applicable Strategies Against Cancer, Type II Diabetes, and Neurodegenerative Diseases by Means of Rationally Designed Anti-Amyloidogenic Molecules].

An increasing number of amyloidogenic proteins are being recognized for their contribution to the progression of various diseases, including cancer, type II diabetes, and neurodegenerative diseases. Detailed analyses of amyloids using cryo-electron microscopy have led to the development of rationally designed inhibitors of amyloid protein aggregation. In this review, we focused on widely applicable strategies against multiple amyloidogenic proteins based on the use of engineered molecules, namely peptidomimetic foldamers, steric zipper inhibitory peptides, di-phenyl-pyrazole derivatives, and chemicals involved in the disaggregation of amyloid fibrils.

Therapeutic Potential of -Synuclein Evolvability for Autosomal Recessive Parkinson's Disease.

The majority of Parkinson's disease (PD) is sporadic in elderly and is characterized by -synuclein (S) aggregation and other alterations involving mitochondria, ubiquitin-proteasome, and autophagy. The remaining are familial PD associated with gene mutations of either autosomal dominant or recessive inheritances. However, the former ones are similar to sporadic PD, and the latter ones are accompanied by impaired mitophagy during the reproductive stage.

Diabetes, inflammation, and the adiponectin paradox: Therapeutic targets in SARS-CoV-2.

Aging and pre-existing conditions in older patients increase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severity and its complications, although the causes remain unclear. Apart from acute pulmonary syndrome, Coronavirus 2019 (COVID-19) can increasingly induce chronic conditions. Importantly, SARS-CoV-2 triggers de novo type 2 diabetes mellitus (T2DM) linked to age-associated cardiovascular disease (CVD), cancers, and neurodegeneration.

Therapeutic Potential of αS Evolvability for Neuropathic Gaucher Disease.

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, . In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3.

Adiponectin paradox as a therapeutic target of the cancer evolvability in aging.

Recent study suggests that protofibril-formation of amyloidogenic proteins (APs) might be involved in evolvability, an epigenetic inheritance of multiple stresses, in various biological systems. In cancer, evolvability of multiple APs, such as p53, γ-synuclein and the members of the calcitonin family of peptides, might be involved in various features, including increased cell proliferation, metastasis and medical treatment resistance. In this context, the objective of this paper is to explore the potential therapeutic benefits of reduced APs evolvability against cancer.

Connecting Alzheimer's Disease With Diabetes Mellitus Through Amyloidogenic Evolvability.

Type 2 diabetes mellitus (T2DM) has been clearlylinked to oxidative stress and amylin amyloidosis in pancreatic β-cells. Yet despite extensive investigation, the biological significance of this is not fully understood. Recently, we proposed that Alzheimer's disease (AD)-relevant amyloidogenic proteins (APs), such as amyloid-β (Aβ) and tau, might be involved in evolvability against diverse stressors in the brain.

Adiponectin Paradox as a Therapeutic Target in Alzheimer's Disease.

Despite the apparent neurotoxicity of amyloid-β (Aβ), recent clinical trials of Aβ immunotherapy have not shown any clinical benefit in Alzheimer's disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD.

Amyloid Evolvability and Cancer.

p53 and γ-synuclein are two major regulators of cancer pathogenesis that have the propensity to form amyloid-like fibrils reminiscent of those in neurodegenerative diseases. Here we propose that fibril formation by these amyloidogenic molecules reflects evolvability, an acquired epigenetic inheritance that may be involved in cancer proliferation, drug resistance, and metastasis.

Understanding Creutzfeldt-Jackob disease from a viewpoint of amyloidogenic evolvability.

Creutzfeldt-Jackob disease (CJD), the most common human prion disorder, is frequently accompanied by ageing-associated neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease. Although cross-seeding of amyloidogenic proteins (APs), including amyloid β and α-synuclein, may be critical in the co-morbidity of neurodegenerative disorders, the direct interaction of APs with prion protein (PrP), the central molecule involved in the pathogenesis of CJD, is unlikely. Currently, the nature of this biological interaction and its significance remain obscure.

Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein.

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer's disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of β-synuclein (βS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which βS mutations promote DLB pathogenesis remain elusive.

Adiponectin Paradox in Alzheimer's Disease; Relevance to Amyloidogenic Evolvability?

Adiponectin (APN) is a multi-functional adipokine which sensitizes the insulin signals, stimulates mitochondria biogenesis, and suppresses inflammation. By virtue of these beneficial properties, APN may protect against metabolic syndrome, including obesity and type II diabetes mellitus. Since these diseases are associated with hypoadiponectinemia, it is suggested that loss of function of APN might be involved.

Possible Role of Amyloid Cross-Seeding in Evolvability and Neurodegenerative Disease.

Aging-related neurodegenerative disorders are frequently associated with the aggregation of multiple amyloidogenic proteins (APs), although the reason why such detrimental phenomena have emerged in the post-reproductive human brain across evolution is unclear. Speculatively, APs might provide physiological benefits for the human brain during developmental/reproductive stages. Of relevance, it is noteworthy that cross-seeding (CS) of APs has recently been characterized in cellular and animal models of neurodegenerative disease, and that normal physiological CS of multiple APs has also been observed in lower organisms, including yeast and bacteria.

Current and future clinical utilities of Parkinson's disease and dementia biomarkers: can they help us conquer the disease?

: Biomarkers for Parkinson's disease and Alzheimer's disease are essential, not only for disease detection, but also provide insight into potential disease relationships leading to better detection and therapy. As metabolic disease is known to increase neurodegeneration risk, such mechanisms may reveal such novel targets for PD and AD. Moreover, metabolic disease, including insulin resistance, offer novel biomarker and therapeutic targets for neurodegeneration, including glucagon-like-peptide-1, dipeptidyl peptidase-4 and adiponectin.

Transgenerational Interaction of Alzheimer's Disease with Schizophrenia through Amyloid Evolvability.

Alzheimer's disease (AD), the most common neurodegenerative dementia, leads to memory dysfunction due to widespread neuronal loss associated with aggregation of amyloidogenic proteins (APs), while schizophrenia (SCZ) represents a major psychiatric disorder characterized by delusions, hallucinations, and other cognitive abnormalities, the underlying mechanisms of which remain obscure. Although AD and SCZ partially overlap in terms of psychiatric symptoms and some aspects of cognitive impairment, the causal relationship between AD and SCZ is unclear. Based on the similarity of APs with yeast prion in terms of stress-induced protein aggregation, we recently proposed that evolvability of APs might be an epigenetic phenomenon to transmit stress information of parental brain to cope with the stressors in offspring.

Motor and Nonmotor Symptoms of Parkinson's Disease: Antagonistic Pleiotropy Phenomena Derived from -Synuclein Evolvability?

Lewy body diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as -synuclein (S) and amyloid- (A) in the brain.

Possible Role of the Polyglutamine Elongation in Evolution of Amyloid-Related Evolvability.

The polyglutamine (polyQ) diseases, such as Huntington's disease and the spinocerebellar ataxias, are characterized by the accumulation of elongated polyQ sequences (epolyQ) and mostly occur during midlife. Considering that polyQ disorders have not been selected out in evolution, there might be important physiological functions of epolyQ during development and/or reproduction. In a similar context, the physiological functions of neurodegeneration-associated amyloidogenic proteins (APs), such as β-amyloid in Alzheimer's disease and α-synuclein in Parkinson's disease, remain elusive.

Early manifestation of depressive-like behavior in transgenic mice that express dementia with Lewy body-linked mutant β-synuclein.

Aim: We previously generated transgenic (Tg) mice that expressed P123H β-synuclein (βS), a dementia with Lewy body-linked mutant βS. Notably, these mice recapitulated neurodegenerative features of Lewy body disease, reflected by motor dysfunction, greater protein aggregation, and memory impairment. Since recent studies suggested that non-motor symptoms, such as depression, might be manifested in the prodromal stage of Lewy body disease, the main objective of the present study was to investigate the early expression of behavior in P123H βS Tg mice.

Evolvability and Neurodegenerative Disease: Antagonistic Pleiotropy Phenomena Derived from Amyloid Aggregates.

At present, the precise physiological role of neurodegenerative disease-related amyloidogenic proteins (APs), including α-synuclein in Parkinson's disease and β-amyloid in Alzheimer's disease, remains unclear. Because of similar adaptability of both human brain neurons and yeast cells to diverse environmental stressors, we previously proposed that the concept of evolvability in yeast prion could also be applied to APs in human brain. However, the mechanistic relevance of evolvability to neurodegenerative disorders is elusive.

Dual-therapy strategy for modification of adiponectin receptor signaling in aging-associated chronic diseases.

Given the paradigm of anti-insulin resistance in therapies for metabolic syndrome, there has been considerable interest in adiponectin (APN), an adipocyte-derived sensitizer of insulin receptor signaling. In contrast to hypoadiponectinemia in metabolic syndrome, evidence suggests that Alzheimer's disease (AD) and other diseases, including chronic heart failure (CHF) and chronic kidney disease (CKD), are characterized by hyperadiponectinemia as well as the APN/obesity paradoxes, indicating that a decrease in APN might also be beneficial for these diseases. Thus, distinct from metabolic syndrome, it is anticipated that APN receptor antagonists rather than agonists might be effective in therapy for some chronic diseases.

Evolvability of Amyloidogenic Proteins in Human Brain.

Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-β and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast.

Potential Application of Centrifuges to Protect the CNS in Space and on Earth.

Objective: Centrifuges are the principal means of generating physiological hypergravity and have been used for many medical purposes, including the therapy of psychiatric diseases and evaluation of vestibular system in the pilots. In particular, modern centrifuges have evolved into mechanically sophisticated precision instruments compared to primitive ones in old times, indicating that centrifuges might possess great potential in modern medicine. Indeed, studies are in progress to apply centrifuges to musculoskeletal degenerative diseases, such as osteoporosis and sarcopenia.

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease.

A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration.

Combined immunotherapy with "anti-insulin resistance" therapy as a novel therapeutic strategy against neurodegenerative diseases.

Protein aggregation is a pathological hallmark of and may play a central role in the neurotoxicity in age-associated neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Accordingly, inhibiting aggregation of amyloidogenic proteins, including amyloid β and α-synuclein, has been a main therapeutic target for these disorders. Among various strategies, amyloid β immunotherapy has been extensively investigated in Alzheimer's disease, followed by similar studies of α-synuclein in Parkinson's disease.