Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: Sept. 1, 2023

Liquid–liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for assembly functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result ribonucleoprotein (RNP) which are critical processing, mRNA transport, stability, stress granule assembly, translation. Stress granules, neuronal transport processing bodies examples cytoplasmic RNP while nucleolus Cajal representative nuclear condensates. In neurons, condensates promote long-range local translation dendrites axon, essential spatiotemporal regulation gene expression, axonal integrity synaptic function. Mutations RBPs pathologic mislocalization aggregation hallmarks several neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease. ALS/FTD-linked mutations alter strength reversibility multivalent with other RNAs, resulting aberrant transitions. These have detrimental consequences on localization, translation, ultimately lead to compromised function Pathogenic protein is dependent various factors, dynamically arrested may serve an initial nucleation step aggregate formation. Recent studies focused identifying mechanisms by neurons resolve transitioned prevent pathogenic inclusions/aggregates. The present review focuses disease-linked RBPs, physiological functions role transitions disease, particularly ALS/FTD. We examine cellular contribute resolution potential therapeutic approaches aberrantly at a molecular level.

Language: Английский

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Small molecules in regulating protein phase separation

Acta Biochimica et Biophysica Sinica, Journal Year: 2023, Volume and Issue: 55(7), P. 1075 - 1083

Published: June 1, 2023

Biomolecular condensates formed by phase separation are involved in many cellular processes. Dysfunctional or abnormal closely associated with neurodegenerative diseases, cancer and other diseases. Small molecules can effectively regulate protein modulating the formation, dissociation, size material properties of condensates. Discovery small to provides chemical probes for deciphering underlying mechanism potential novel treatments condensate-related Here we review advances molecule regulation separation. The discovery, structures recently found regulators how they modulate biological summarized discussed. Possible strategies accelerate discovery more liquid-liquid (LLPS)-regulating proposed.

Language: Английский

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From zinc homeostasis to disease progression: Unveiling the neurodegenerative puzzle

Pharmacological Research, Journal Year: 2023, Volume and Issue: 199, P. 107039 - 107039

Published: Dec. 19, 2023

Zinc is a crucial trace element in the human body, playing role various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- Irt-like proteins (ZIPs) involved importing extracellular zinc. These essential maintaining cellular homeostasis. Imbalances metabolism have been linked to development of neurodegenerative diseases. Disruptions levels can impact survival activity neurons, thereby contributing progression diseases through mechanisms like cell apoptosis regulation, phase separation, ferroptosis, neuroinflammation. Therefore, conducting systematic review regulatory network investigating relationship between dysmetabolism enhance our understanding pathogenesis these Additionally, it may offer new insights approaches treatment

Language: Английский

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Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 75, P. 102333 - 102333

Published: May 31, 2023

Language: Английский

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Protein conformation and biomolecular condensates

Current Research in Structural Biology, Journal Year: 2022, Volume and Issue: 4, P. 285 - 307

Published: Jan. 1, 2022

Protein conformation and cell compartmentalization are fundamental concepts subjects of vast scientific endeavors. In the last two decades, we have witnessed exciting advances that unveiled conjunction these concepts. An avalanche studies highlighted central role biomolecular condensates in membraneless subcellular permits spatiotemporal organization regulation myriads simultaneous biochemical reactions macromolecular interactions. These also shown condensation, driven by multivalent intermolecular interactions, is mediated order-disorder transitions protein domain architecture. Conceptually, condensation a distinct level conformational landscape which collective folding large collections molecules takes place. Biomolecular arise physical process phase separation comprise variety bodies ranging from organelles to liquid solid-like conglomerates, spanning lengths mesoscopic clusters (nanometers) micrometer-sized objects. this review, summarize discuss recent work on assembly, composition, conformation, material properties, thermodynamics, regulation, functions bodies. We review conceptual framework for future dynamics condensed proteins cellular processes.

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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Aggregation mechanisms and molecular structures of amyloid‐β in Alzheimer’s disease

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(48)

Published: Aug. 2, 2024

Amyloid plaques are a major pathological hallmark involved in Alzheimer's disease and consist of deposits the amyloid-β peptide (Aβ). The aggregation process Aβ is highly complex, which leads to polymorphous aggregates with different structures. In addition aberrant aggregation, oligomers can undergo liquid-liquid phase separation (LLPS) form dynamic condensates. It has been hypothesized that these amyloid liquid droplets affect modulate fibril formation. this review, we briefly introduce relationship between stress granules protein associated neurodegenerative diseases. Then highlight regulatory role LLPS discuss potential transition aggregation. Furthermore, summarize current structures fibrils, have determined using nuclear magnetic resonance (NMR) cryo-electron microscopy (cryo-EM). structural variations provide an explanation for levels toxicity, shed light on mechanism may pave way towards structure-based drug design both clinical diagnosis treatment.

Language: Английский

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Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: March 5, 2025

Abstract Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving formation of this pathology relationship with SNc dopamine neuron health are yet to be fully understood. We applied proteomic mass spectrometry synchrotron-based biometal quantification post-mortem brain tissues from disease patients age-matched controls uncover key factors underlying SOD1 disorder. also engineered two these - copper deficiency upregulated levels into a novel mouse strain, termed SOCK mouse, verify their involvement development Parkinson-like impact on health. Soluble exhibited altered post-translational modifications, which may underlie changes enzymatic activity aggregation region. These include decreased binding, dysregulation physiological glycosylation, atypical oxidation glycation amino acid residues. demonstrated that biochemical profile introduced mice promotes same modifications midbrain cortex. This accumulates progressively age is accompanied by nigrostriatal degeneration dysfunction, occur absence α-synuclein deposition. do not exhibit weight loss nor spinal cord motor degeneration, distinguishing them transgenic mutant models. study provides first vivo evidence mismetallation precipitates misfolding, brain, contribute degeneration. Our data position as drug target for disorder, particular focus therapies capable correcting alterations modifications.

Language: Английский

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HuR prevents amyloid beta-induced phase separation of miRNA-bound Ago2 to RNA-processing bodies

Structure, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Multivalent interaction induces phase separation and formation of more toxic aggregates of α-syn in a yeast model of Parkinson’s disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 18, 2025

Abstract The process of protein phase separation, particularly in the context intrinsically disordered proteins, has been extensively studied for its implications several neuro-degenerative diseases. Although mechanism separation and involved molecular grammar have well explored under vitro conditions, focus is now shifting towards developing more complex models order to mimic biological systems closely. Here, we alpha synuclein (α-syn), an whose aggregation implicated pathology Parkinson’s Disease, (PD) inside yeast cells ( Saccharomyces cerevisiae ). Using a positively charged polymer; polyethylenimine (PEI), which binds presumably at negatively C-terminal domain α-syn, find that α-syn can be modulated by least two pathways: one involving second without separation. We further these pathways lead varying fibril characteristics toxicities. believe this model used as quick convenient system screen novel repurposed small molecules against toxic droplets.

Language: Английский

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