Alzheimer and Parkinson diseases, frontotemporal lobar degeneration and amyotrophic lateral sclerosis overlapping neuropathology start in the first two decades of life in pollution exposed urbanites and brain ultrafine particulate matter and industrial nanoparticles, including Fe, Ti, Al, V, Ni, Hg, Co, Cu, Zn, Ag, Pt, Ce, La, Pr and W are key players. Metropolitan Mexico City health crisis is in progress

Frontiers in Human Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Jan. 12, 2024

The neuropathological hallmarks of Alzheimer’s disease (AD), Parkinson’s (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS) are present in urban children exposed to fine particulate matter (PM 2.5 ), combustion friction ultrafine PM (UFPM), industrial nanoparticles (NPs). Metropolitan Mexico City (MMC) forensic autopsies strongly suggest that anthropogenic UFPM NPs reach the brain through nasal/olfactory, lung, gastrointestinal tract, skin, placental barriers. Diesel-heavy unregulated vehicles a key source for 21.8 million MMC residents. We found hyperphosphorylated tau, beta amyloid 1-42 , α-synuclein, TAR DNA-binding protein-43 were associated with 186 (mean age 27.45 ± 11.89 years). neurovascular unit is an early anatomical target, first two decades life critical: 100% 57 aged 14.8 5.2 years had AD pathology; 25 (43.9%) AD+TDP-43; 11 (19.3%) + PD TDP-43; 2 (3.56%) +PD. Fe, Ti, Hg, Ni, Co, Cu, Zn, Cd, Al, Mg, Ag, Ce, La, Pr, W, Ca, Cl, K, Si, S, Na, C seen frontal temporal lobes, olfactory bulb, caudate, substantia nigra, locus coeruleus, medulla, cerebellum, and/or motor cortical spinal regions. Endothelial, neuronal, glial damages extensive, mitochondria, rough endoplasmic reticulum, Golgi apparatus, lysosomes. Autophagy, cell nuclear membrane damage, disruption pores heterochromatin, death present. Metals abrasion deterioration automobile catalysts electronic waste rare earth elements, i.e., lanthanum, cerium, praseodymium, entering young brains. Exposure environmental prime candidates initiating stages fatal neurodegenerative diseases. adults—surrogates polluted areas around world—exhibit AD, PD, FTLD, ALS forecasting serious health, social, economic, academic, judicial societal detrimental impact. Neurodegeneration prevention should be public health priority as problem human exposure particle pollution solvable. knowledgeable main emission sources technological options control them. What we waiting for?

Language: Английский

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Friend or foe: The role of stress granule in neurodegenerative disease

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2464 - 2485

Published: May 13, 2024

Language: Английский

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Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: March 26, 2024

Proteinopathy, defined as the abnormal accumulation of proteins that eventually leads to cell death, is one most significant pathological features neurodegenerative diseases. Tauopathies, represented by Alzheimer's disease (AD), and synucleinopathies, Parkinson's (PD), show similarities in multiple aspects. AD manifests extrapyramidal symptoms while dementia also a major sign advanced PD. We other researchers have sequentially shown cross-seeding phenomenon α-synuclein (α-syn) tau, reinforcing pathologies between synucleinopathies tauopathies. The highly overlapping clinical imply shared pathogenic mechanisms two groups disease. diagnostic therapeutic strategies seemingly appropriate for distinct may apply broader spectrum. Therefore, clear understanding overlaps divergences tauopathy synucleinopathy critical unraveling nature complicated associations among In this review, we discuss diverse characteristics tauopathies from aspects genetic causes, manifestations, progression potential common approaches targeting pathology, aim provide timely update setting scheme classification novel insights into development

Language: Английский

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RNA G-quadruplexes and calcium ions synergistically induce Tau phase transitionin vitro

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

Published: March 3, 2024

Abstract Tau aggregation is a defining feature of neurodegenerative tauopathies, including Alzheimer’s disease, corticobasal degeneration, and frontotemporal dementia. This involves the liquid–liquid phase separation (LLPS) Tau, followed by its sol–gel transition, representing crucial step in aggregate formation both vitro vivo . However, precise cofactors influencing transition under physiological conditions (e.g., ion concentration temperature) remain unclear. In this study, we unveil that nucleic acid secondary structures, specifically RNA G-quadruplexes (rG4s), calcium ions (Ca 2+ ) synergistically facilitated human mimic intracellular (140 mM KCl, 15 NaCl, 10 MgCl 2 at 37□ presence molecular crowding reagents, formed stable liquid droplets through LLPS, maintaining fluidity for 24 h conditions. Notably, cell-derived promoted with G4-forming emerging as factor. Surprisingly, polyanion heparin did not elicit similar response, indicating distinct mechanism rooted electrostatic interactions. Further exploration underscored significance Ca , which accumulate intracellularly during neurodegeneration, additional promoting after h. Importantly, our findings demonstrate rG4s enhance within 1 when introduced to droplets. conclusion, study illuminates pivotal roles offering insights into potential triggers tauopathy.

Language: Английский

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Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 18, 2024

Abstract Once considered unconventional cellular structures, membraneless organelles (MLOs), substructures involved in biological processes or pathways under physiological conditions, have emerged as central players dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, metabolism to cancer, influence on human health disease extends widely. This review discusses underlying mechanisms LLPS, biophysical properties that drive MLO formation, their implications for We highlight recent advances understanding how physicochemical environment, molecular interactions, post-translational modifications regulate LLPS dynamics. offers an overview discovery current biomolecular condensate conditions diseases. article aims deliver latest insights by analyzing research, highlighting critical role organization. The discussion also covers membrane-associated condensates cell signaling, including those involving T-cell receptors, stress granules linked lysosomes, within Golgi apparatus. Additionally, potential targeting clinical settings is explored, promising avenues future research therapeutic interventions.

Language: Английский

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Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Jan. 4, 2024

The nematode Caenorhabditis elegans are a powerful model system to study human disease, with numerous experimental advantages including significant genetic and cellular homology vertebrate animals, short lifespan, tractable behavioral, molecular biology imaging assays. Beginning the identification of SOD1 as cause amyotrophic lateral sclerosis (ALS), C. have contributed deeper understanding mechanistic underpinnings this devastating neurodegenerative disease. More recently work has expanded encompass models other types ALS related disease frontotemporal lobar degeneration (FTLD-TDP), those characterized by mutation or accumulation proteins TDP-43, C9orf72, FUS, HnRNPA2B1, ALS2, DCTN1, CHCHD10, ELP3, TUBA4A, CAV1, UBQLN2, ATXN3, TIA1, KIF5A, VAPB, GRN, RAB38. In review we summarize these progress insights from last ten years using diseases FTLD-TDP.

Language: Английский

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Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(10), P. 5756 - 5773

Published: April 8, 2024

Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking display damage with a subset of these cells bypassing senescence to initiate break-induced (BIR) synthesis. Here we show that the abnormal stabilization G4 following depletion leads repeat-containing RNA (TERRA)-R-loop accumulation, triggering liquid-liquid phase separation (LLPS) assembly Alternative Lengthening Telomeres (ALT)-associated promyelocytic leukemia (PML) bodies (APBs). Disruption R-loops abolishes LLPS impairs Artificial engineering restores synthesis, underscoring critical role in ALT. TERRA-R-loops also recruit Polycomb Repressive Complex 2 (PRC2), leading tri-methylation Lys27 on histone H3 (H3K27me3) at telomeres. Half paraffin-embedded tissue sections from human breast cancers exhibit APBs length heterogeneity, suggesting mutations can predispose individuals ALT-type tumorigenesis. Overall, abrogation disrupts dynamicity G4, producing TERRA-R-loops, finally liquid condensates We propose modulating targeting maintenance may represent effective therapeutic strategies treating ALT-like APBs, including those disruptions.

Language: Английский

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Liquid-liquid phase separation in subcellular assemblages and signaling pathways: Chromatin modifications induced gene regulation for cellular physiology and functions including carcinogenesis

Biochimie, Journal Year: 2024, Volume and Issue: 223, P. 74 - 97

Published: May 7, 2024

Language: Английский

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Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 6, 2025

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed condensation proteins, nucleic acids, other molecules-in driving efficient dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression intracellular signal transduction, enabling rapid finely tuned responses. Their ability regulate signaling pathways is particularly significant, it requires a careful balance between flexibility precision. Disruption this can lead pathological conditions, including neurodegenerative diseases, cancer, viral infections. Consequently, emerged promising therapeutic targets, with potential offer novel approaches disease treatment. In review, we present recent insights into regulatory mechanisms by which influence pathways, roles health disease, strategies for modulating condensate dynamics approach. Understanding these emerging principles may provide valuable directions developing effective treatments targeting aberrant behavior diseases.

Language: Английский

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Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 12

Published: Feb. 7, 2025

Neurodegenerative diseases are characterized by the progressive breakdown of neuronal structure and function pathological accumulation misfolded protein aggregates toxic oligomers. A major contributor to deterioration physiology is disruption catabolic pathways mediated proteasome, a large protease complex responsible for most cellular degradation. Previously, it was believed that proteolysis proteasome required tagging targets with polyubiquitin chains, pathway called ubiquitin-proteasome system (UPS). Because this, research on proteasomal roles in neurodegeneration has historically focused UPS. However, additional ubiquitin-independent their importance increasingly recognized. In this review, we discuss range pathways, focusing substrate identification targeting, regulatory molecules adaptors, activators alternative caps, diverse complexes including 20S membrane immunoproteasome, extracellular proteasomes, hybrid proteasomes. These further discussed context aging, oxidative stress, aggregation, age-associated neurodegenerative diseases, special focus Alzheimer's Disease, Huntington's Parkinson's Disease. mechanistic understanding regulation critical development therapies treat these devastating conditions. This review summarizes current state neurodegeneration.

Language: Английский

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