Structural insights and milestones in TDP-43 research: A comprehensive review of its pathological and therapeutic advances

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 141677 - 141677

Published: March 1, 2025

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a critical RNA/DNA-binding involved in various cellular processes, including RNA splicing, transcription regulation, and stability. Mislocalization aggregation of TDP-43 the cytoplasm are key features pathogenesis several neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD). This review provides comprehensive retrospective prospective analysis research, highlighting structural insights, significant milestones, evolving understanding its physiological pathological functions. We delineate five major stages from initial discovery as hallmark neurodegeneration to recent advances liquid-liquid phase separation (LLPS) behavior interactions with processes. Furthermore, we assess therapeutic strategies targeting pathology, categorizing approaches into direct indirect interventions, alongside modulating aberrant LLPS. propose that future research will focus on three areas: polymorphisms for disease-specific therapeutics, exploring dual temporal-spatial modulation TDP-43, advancing nano-therapy. More importantly, emphasize importance TDP-43's functional repertoire at mesoscale, which bridges molecular functions broader offers foundational framework development.

Language: Английский

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Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration

Cells, Journal Year: 2024, Volume and Issue: 13(3), P. 286 - 286

Published: Feb. 5, 2024

The key to the effective treatment of neurodegenerative disorders is a thorough understanding their pathomechanism. Neurodegeneration and neuroinflammation are mutually propelling brain processes. An impairment glymphatic system function in neurodegeneration contributes progression pathological question arises as how related. This review highlights direct indirect influence these two seemingly independent Protein aggregates, characteristic feature neurodegeneration, correlated with clearance neuroinflammation. Glial cells cannot be overlooked when considering neuroinflammatory Astrocytes essential for functioning play crucial role inflammatory responses central nervous system. It imperative acknowledge significance AQP4, protein that exhibits high degree polarization astrocytes AQP4 influences processes have not yet been clearly delineated. Another interesting issue gut–brain axis microbiome, which potentially impact discussed A discussion correlation between may contribute exploring pathomechanism neurodegeneration.

Language: Английский

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The Bidirectional Relationship between Sleep and Neurodegeneration: Actionability to Improve Brain Health

Clinical and Translational Neuroscience, Journal Year: 2024, Volume and Issue: 8(1), P. 11 - 11

Published: Feb. 2, 2024

Recently, it has become increasingly clear that there is a bidirectional relationship between sleep/circadian rhythms and neurodegeneration. Knowledge about this topic further improved after the description of glymphatic system, which mainly active during sleep. Changes in sleep circadian are present not only overt neurodegenerative diseases but also their early, prodromal, preclinical phases, supporting they precede (and contribute to) development This narrative review provides brief overview rhythm disruption neurodegeneration, highlights changes addresses future perspectives, particular, whether able to predict neurodegeneration potential actionability prevent or modulate diseases.

Language: Английский

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Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity

Frontiers in Aging, Journal Year: 2025, Volume and Issue: 6

Published: May 21, 2025

The relationship between sleep and metabolism has emerged as a critical factor in aging age-related diseases, including Alzheimer’s disease dementia. Mitochondrial oxidative phosphorylation, essential for neuronal energy production, also generates reactive oxygen species (ROS), which increase with age contribute to stress. Sleep plays vital role modulating redox balance, facilitating the clearance of free radicals, supporting mitochondrial function. Disruptions are closely linked imbalances, emerging evidence suggests that pharmacological interventions, such dual orexin receptor antagonists antioxidant-based therapies, may help restore homeostasis. Furthermore, antioxidant-rich diets supplements have shown promise improving both quality metabolic health populations. Neurons, their high demands, particularly vulnerable damage, making regulation crucial maintaining brain integrity. This review explores bidirectional through five key areas: (1) sleep’s radical regulation, (2) ROS mediators disturbances, (3) feedback loops impaired metabolism, (4) sleep, redox, peripheral systems, (5) therapeutic strategies balance improve outcomes. Understanding these mechanisms provide new targets interventions aimed at mitigating age-associated diseases.

Language: Английский

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Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

Exploration of neuroscience, Journal Year: 2025, Volume and Issue: 4

Published: March 24, 2025

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on global scale. One the main molecular mechanisms responsible for development Neuro-PASC, individuals all ages, is formation inadequate proteolysis/clearance phase-separated amyloid crystalline aggregates—a hallmark feature aging-related neurodegenerative disorders. Amyloidogenesis during viral persistence natural, inevitable, protective defense response exacerbated by SARS-CoV-2. Acting as chemical catalyst, accelerates hydrophobic collapse heterogeneous nucleation amorphous amyloids into stable β-sheet aggregates. clearance aggregates most effective slow wave sleep, when high levels adenosine triphosphate (ATP)—a biphasic modulator biomolecular condensates—and melatonin are available solubilize removal. dysregulation mitochondrial dynamics SARS-CoV-2, particular fusion fission homeostasis, impairs proper distinct subpopulations can remedy challenges created diversion substrates away from oxidative phosphorylation towards glycolysis support replication maintenance. subsequent reduction ATP inhibition synthesis sleep results incomplete brain aggregates, leading commonly associated age-related Exogenous not only prevents dysfunction but also elevates production, effectively augmenting solubilizing effect moiety ensure timely, optimal disaggregation pathogenic prevention attenuation Neuro-PASC.

Language: Английский

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Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system

Frontiers in Psychiatry, Journal Year: 2024, Volume and Issue: 15

Published: April 8, 2024

The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates exchange of cerebrospinal and interstitial fluid, aiding soluble proteins metabolites distributing essential nutrients signaling molecules. Emerging evidence suggests link between dysfunction pathogenesis neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's disease. These disorders are characterized by accumulation propagation misfolded or mutant proteins, process which likely involved. Impaired could lead to buildup these toxic contributing neurodegeneration. Understanding system's role provide insights into their pathophysiology pave way new therapeutic strategies. Pharmacological enhancement reduce burden slow disease progression. Neuroimaging techniques, particularly MRI-based methods, have emerged as promising tools studying

Language: Английский

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How sleep quality affects activities of daily living in Parkinson’s disease: the mediating role of disease severity and the moderating role of cognition

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Sept. 29, 2023

The aim of this study was to explore the influential mechanism relationship between sleep quality and activities daily living (ADL) in patients with Parkinson's disease (PD), we hypothesized severity as a mediator assumed mediating process regulated by cognition.194 individuals PD (95 women 99 men) were enrolled study. Pittsburgh Sleep Quality Index (PSQI) used assess patients. Patients' ADL, cognition measured Unified Disease Rating Scale-II (UPDRSII), Hoehn-Yahr (H-Y) Scale, Mini-Mental State Examination (MMSE). We investigated role moderating effect on association ADL patients.The score UPDRSII positively correlated PSQI H-Y stage, while MMSE negatively stage UPDRSII. predicts severity, ADL. mediated 0.179. Cognition alone did not affect but interaction significantly affected confirming patients.Disease good reduced severity's influence Our indicated close PD, also provided new insights into overall management better life

Language: Английский

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Interpretation of brain health impairment due to sleep disturbances of the glymphatic system

Salud Ciencia y Tecnología, Journal Year: 2024, Volume and Issue: 4, P. 927 - 927

Published: April 4, 2024

Sleep is an essential biological cycle that regulates the internal rhythms of human being and contributes to maintaining homeostasis. During sleep, glymphatic system, responsible for eliminating brain waste, activated. deprivation or related disorders can slow down elimination beta-amyloid protein, increasing risk cognitive impairment, dementia Alzheimer's disease. This study sought interpret how alterations in system during sleep affect health. A literature review was conducted using document analysis techniques, analyzing scientific articles Virtual Health Library, Lilacs, PubMed various indexed journals. Search strategies based on descriptors Boolean operators were developed period from August September 2023. As results, a connection between migraine suggested, observing decrease solutes metabolites prolonged periods wakefulness. bidirectional relationship has also been identified post-traumatic headache disturbances following injury, possibly due dysfunction which limits clearance headache-related neuropeptides its chronicity. Dysfunction present several neurological disorders, as well decreased drainage proinflammatory chemicals cytokines different conditions. It concluded these findings suggest could be considered diagnostic therapeutic avenue diseases previously chronic irreversible

Language: Английский

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Regional Glymphatic Dysfunction is linked to Spinocerebellar Ataxia Type 3 pathophysiology

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 20, 2024

Abstract Spinocerebellar ataxia type 3 (SCA3) involves neuroinflammation and imbalance between production clearance of proteins which affects the glymphatic system, lymphatic-like, fluid-transport system in brain. However, it is unclear whether SCA3 related to impairments function. Using multimodal imaging data, 34 patients 36 age-, sex- educational matched healthy controls (HCs) were compared using multiple measurements, including choroid plexus (CP) cerebrospinal fluid (CSF) volume, diffusion tensor along perivascular (DTI-ALPS) index, coupling relationship blood-oxygen-level-dependent signals CSF flow (BOLD-CSF coupling). Then, we evaluated regional function by dividing DTI-ALPS BOLD-CSF into anterior, middle, posterior, cerebellum regions, thereby identifying spatial variation two groups. We demonstrated that with HCs, larger CP volumes found patients. More importantly, for index coupling, these surrogate markers weaker Furthermore, altered functions most prominent midbrain, middle regions. Crucially, cerebellum, global accompanied severity other symptoms. Similar neurodegenerative disorders, association indexes symptoms suggested waste disrupted patients, shed light on pathogenesis this disease from a lens. Our findings highlighted dysregulated as novel diagnostic marker SCA3.

Language: Английский

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Lebensstiländerungen im Alter und ihr potenzieller Einfluss auf das primäre Offenwinkelglaukom

Klinische Monatsblätter für Augenheilkunde, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 27, 2024

Zusammenfassung Das primäre Offenwinkelglaukom ist eine Mitochondriopathie, die über den oxidativen Stress zu einer Neuroinflammation führt und später in Neurodegeneration übergeht. Dabei sind neben dem visuellen System zahlreiche weitere Hirnareale betroffen. Da es beim Altern im Rahmen mitochondrialen Dysfunktion ebenfalls niedriggradigen chronischen Entzündungsreaktion kommt (Inflamm-Aging), überlagern sich diese entzündlichen Prozesse Alter verstärken glaukomassoziierten pathophysiologischen Vorgänge. Um aktiv diesen Entzündungsereignissen entgegenzuwirken, soll Therapie von vorhandenen Systemerkrankungen optimiert, Chronobiologie eingehalten das Mikrobiom verbessert werden. Hierfür unterstützend erhöhte physische mentale Aktivität. Somit personalisierten zieldruckorientierten Augeninnendrucksenkung auch holistische Sichtweise erforderlich, um der primäres therapeutisch gerecht

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