Sub-cellular biochemistry最新文献

Seed amplification assays (SAAs) are highly sensitive and advanced techniques originally developed for the study and diagnosis of prion diseases. Thanks to their remarkably high sensitivity and specificity, SAAs are now widely employed in both research and clinical settings for prion detection, especially in peripheral tissues of patients with prion disorders. Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and amyotrophic lateral sclerosis, show prion-like mechanisms involving the misfolding and self-propagation of pathological proteins. As a result, SAAs are being adapted and refined for clinical use to improve the diagnosis of these conditions. This includes detecting traces of pathological proteins in cerebrospinal fluid as well as in minimally or noninvasively collected samples, such as blood, urine, skin, and olfactory mucosa. This chapter offers an overview of the role of SAAs in the clinical diagnosis of neurodegenerative diseases.

Nuclear lamins, the unique type 5 intermediate filaments of the nucleus, form a structural network beneath the nuclear envelope. Through their strategic localization, they interact with numerous partners and regulate a wide range of biochemical and biophysical processes. In load-bearing tissues such as the heart, nuclear lamins are crucial for maintaining mechanical integrity and genome stability during cardiac contraction. By associating with chromatin through lamina-associated domains, they play a fundamental role in genome organization and gene expression. Disruption of the nuclear lamin meshwork in CardioLaminopathy leads to chromatin remodeling and dysregulated gene expression. Although the precise cellular and molecular mechanisms driving CardioLaminopathy remain incompletely understood, alterations in genome organization are emerging as key contributors to disease pathogenesis and progression.

Misfolded protein neurodegeneration includes several pathologies characterized by the accumulation of a group of proteins that can modify their folding due to intrinsic or extrinsic factors, leading to the generation of aberrant forms characterized by their high insolubility, cytotoxicity, and the ability to propagate among various cell types and regions in affected brains. Due to this capacity and based on the properties of bona fide prions, a large number of "prion-like" or "prionoid" proteins with this ability have been described in recent years. Their study presents challenges, including the development of a detailed understanding of the processes involved in the formation of these insoluble aggregates and in establishing the cellular and molecular bases underlying the process of intercellular propagation. To address these processes, various laboratories have developed techniques to detect their presence in brain or peripheral samples. The detection of these molecules is, as of today, very effective and selective. However, the processes of transmission and propagation are not fully characterized. Indeed, various classical detection techniques have been developed, generally based on controlled polymerization processes and effective detection methods. Nevertheless, these conventional techniques have now incorporated various methodologies employed in other disciplines, such as nanotechnology, which have increased our understanding of these processes and are useful in the development of future therapies and drug discovery. In this chapter, we summarize the current state of the art of these conventional methods, their limitations, and the use of new platforms to deepen our understanding of these processes.

Schizophrenia is a severe and complex psychiatric condition ranking among the top 15 leading causes of disability worldwide. Despite the well-established heritability component, a complex interplay between genetic and environmental risk factors plays a key role in the development of schizophrenia and psychotic disorders in general. This chapter covers all the clinical evidence showing how the analysis of the epigenetic modulation in schizophrenia might be relevant to understand the pathogenesis of schizophrenia as well as potentially useful to develop new pharmacotherapies.

The brain plays a vital role in maintaining homeostasis and effective interaction with the environment, shaped by genetic and environmental factors throughout neurodevelopment and maturity. While genetic components dictate initial neurodevelopment stages, epigenetics-specifically neuroepigenetics-modulates gene expression in response to environmental influences, allowing for brain adaptability and plasticity. This interplay is particularly evident in neuropathologies like Rett syndrome and CDKL5 deficiency syndrome, where disruptions in neuroepigenetic processes underline significant cognitive and motor impairments. The environmental enrichment paradigm, introduced by Donald Hebb in the late 1940s, demonstrates how enriching stimuli-such as complex sensory, social, and cognitive inputs-affect brain structure and function. Despite methodological variability, evidence reveals that enriched environments catalyze beneficial changes in behavior and neuroanatomy, including increased synaptic plasticity, enhanced motor coordination, and improved cognitive performance in rodent models. Additionally, environmental enrichment induces epigenetic modifications that facilitate these outcomes, highlighting the necessity of understanding the mechanisms driving gene expression changes within the context of enriched experiences. Ultimately, this manifold relationship between environment, neuroepigenetic modulation, and brain function highlights the brain's capacity for change, reinforcing the importance of considering environmental factors in studies of neurodevelopment and therapy for neurological disorders.

Bacterial microcompartments (BMCs) and biomolecular condensates are two different forms of protein compartmentalization with different aims and functional advantages, representing specific designs of sequestering enzymes or segments of metabolic pathways. BMCs represent special proteinaceous organelles that are entirely composed of protein and are typically characterized by polyhedral shapes. By encapsulating and organizing metabolic enzymes with their substrates and cofactors BMCs act as specialized compartments within bacterial cells that promote and enhance specific biochemical pathways. They also serve important protective functions shielding vulnerable enzymes within a defined microenvironment and sequestering toxic or volatile intermediates. On the other hand, biomolecular condensates (also known as membrane-less organelles, MLOs) are dynamic, cell size-dependent, cytoplasmic and nucleoplasmic entities that typically contain both RNA and protein. They have unique morphologies, specific distribution patterns, are characterized by specific set of resident proteins, but their structural integrity is not supported by encapsulation in the membrane. Instead, their biogenesis is driven by liquid-liquid phase separation, and their structure is entirely controlled and mediated by the protein-protein, protein-RNA, and/or protein-DNA interactions. MLOs represent a different liquid state of cytoplasm or nucleoplasm (or mitochondrial matrix or chloroplastic stroma), whose major biophysical properties are rather similar to those of the rest of the intracellular fluid. Often, MLOs emerge in response to some specific environmental cues, being exploited by cells to respond in real time in a smart stimuli-responsive manner. BMCs are more permanent entities with selective transport through the protein shell. In that way and in many respects, they are closer to intracellular membrane-bounded organelles of eukaryotes than to MLOs. This chapter discusses diverse functions of BMCs and considers the ways by which they contribute to metabolic innovation in bacteria. Some functional roles of MLOs are considered as well.

A typical feature of human prion diseases (PrDs) is the rapid decline to terminal illness that patients experience after symptom onset, with the most common phenotype, sporadic Creutzfeldt-Jakob disease (sCJD), frequently progressing from full independence to requiring palliative care over the course of weeks. A similar disease course is often observed in the much less common genetic CJD, especially when associated with the more common pathogenic mutations E200K and D178N. Therefore, the temporal therapeutic window is greatly reduced in PrDs compared with other dementias. There are currently no recognised reliable indicators of imminent or prodromal disease preceding the onset of overt, rapid, and currently unalterable decline. The advent of disease-modifying therapies will further underscore the need to expedite the time taken to achieve an accurate diagnosis in order to improve patient outcomes, highlighting the importance of detecting PrDs as early as possible in their clinical evolution. This review discusses what we currently know about pre-symptomatic and prodromal PrD derived from incidental case reports, limited preclinical cohort studies, and large-scale retrospective tissue screening programmes, contextualising the utility of current diagnostic tools and biomarkers for the detection of PrDs at these nascent disease stages.

Nuclear lamins, a crucial type of intermediate filament protein, primarily form the inner nuclear membrane and are essential for maintaining nuclear integrity throughout various cell cycle stages. However, recent research has uncovered their broader functions as key scaffolds in nuclear sub-compartmentalization, 3D genome organization, and gene regulation. These functions are dynamically regulated by several post-translational modifications (PTMs), including phosphorylation, acetylation, SUMOylation, methylation, ubiquitination, farnesylation, and O-GlcNAcylation. Lamin PTMs influence chromatin stability, nuclear organization, stress responses, cellular differentiation, metabolism, and ageing. The pathological implications of lamin dysfunction are profound. Altered PTM patterns have been associated with multiple disorders, including laminopathies, metabolic syndromes, premature ageing diseases like Hutchinson-Gilford progeria, and even cancer.This chapter discusses how dysregulated lamin PTMs lead to nuclear instability and chromatin disorganization and contribute to disease progression. Understanding how PTMs affect lamin function opens avenues for therapeutic strategies targeting lamin-related disorders. This research is critical for developing innovative treatments aimed at restoring nuclear integrity and normal cellular function, ultimately improving disease outcomes.

Urea transporters (UT) in renal tubule epithelial cells (UT-A) and vasa recta endothelial cells (UT-B) play an important role in the urine concentrating mechanism. Therefore, UTs are regarded as a potential target for diuretics, or 'urearetics', with unique mechanisms of action and clinical indications. UT inhibitors have a diuretic effect without causing disorders of electrolyte balance like classical diuretics that induce diuresis by natriuresis. This chapter delves into the screening and evaluation methods used for discovering UT inhibitors, the small molecule UT inhibitors that have been identified to date, and UT inhibitors' therapeutic effect in hyponatremic animal models. The studies on UT inhibitors as diuretics show promise for treating dilutional hyponatremia associated with conditions like congestive heart failure, cirrhosis, ascites, and nephrotic syndrome, as well as the syndrome of inappropriate antidiuretic hormone (SIADH) secretion.

The human genome consists of 23 chromosome pairs (22 autosomes and one pair of sex chromosomes), with 46 chromosomes in a normal cell. In the interphase nucleus, the 2 m long nuclear DNA is assembled with proteins forming chromatin. The typical mammalian cell nucleus has a diameter between 5 and 15 μm in which the DNA is packaged into an assortment of chromatin assemblies. The human brain has over 3000 cell types, including neurons, glial cells, oligodendrocytes, microglial, and many others. Epigenetic processes are involved in directing the organization and function of the genome of each one of the 3000 brain cell types. We refer to epigenetics as the study of changes in gene function that do not involve changes in DNA sequence. These epigenetic processes include histone modifications, DNA modifications, nuclear RNA, and transcription factors. In the interphase nucleus, the nuclear DNA is organized into different structures that are permissive or a hindrance to gene expression. In this chapter, we will review the epigenetic mechanisms that give rise to cell type-specific gene expression patterns.