Light-Controlled Intracellular Synthesis of Poly(luciferin) Polymers Induces Cell Paraptosis

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

Accumulation of misfolded proteins challenges cellular proteostasis and is implicated in aging chronic disorders. Cancer cells, moreover, face an elevated level basal proteotoxic stress; hence, exacerbating endoplasmic reticulum (ER) stress has been shown to induce programmed cell death while enhancing anticancer immunogenicity. We hypothesize that hydrophobic abiotic macromolecules can trigger a similar response. Most polymers nanoparticles, however, are sequestered endo/lysosomes after endocytosis, which prevents their interaction with the machinery. adopted

Language: Английский

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Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers

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

Published: April 10, 2025

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in paralysis and death within three to five years. Mutations over forty different proteins have been linked ALS, leading controversy whether ALS one or many diseases with similar phenotype. Cu,Zn superoxide dismutase 1 (SOD1) are only found 2-3% of cases, yet misfolded SOD1 both sporadic (sALS) familial (fALS) patients. Yet, mutations TDP-43 FUS increase the level on extracellular vesicles (EVs). Additionally, small EVs isolated from patient samples caused cell wild type motor neurons myotubules. The toxicity protein alterations led theory that responsible for spread ALS. We hypothesize previously-identified toxic trimeric spreading altering other ALS-related proteins, linking them common mechanism. To test our hypothesis, we isolate neuron-like cells expressing trimer stabilizing perform sandwich enzyme-linked immunoassay (ELISA) (CD9 capture antibody) quantify 17 decrease stabilization. identify which EV release pathway being affected by utilizing endocytosis exocytosis inhibitors, determine if any specific EV-related altered establish VAPB, VCP, Stathmin-2 between ALS-associated multiple pathways, including Caveolae pathway, suggesting novel hybrid present

Language: Английский

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The effects of biological crowders on fibrillization, structure, diffusion, and conformational dynamics of α‐synuclein

Protein Science, Journal Year: 2024, Volume and Issue: 33(3)

Published: Feb. 15, 2024

α-synuclein is an intrinsically disordered protein (IDP) whose aggregation in presynaptic neuronal cells a pathological hallmark of Lewy body formation and Parkinson's disease. This process likely affected by the crowded macromolecular cellular environment. In this study, was studied presence both synthetic crowder, Ficoll70, biological crowder composed lysed that better mimics biocomplexity

Language: Английский

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Peptide Self-Assembly into Amyloid Fibrils: Unbiased All-Atom Simulations

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(14), P. 3320 - 3328

Published: March 6, 2024

Protein self-assembly plays an important role in biological systems, accounting for the formation of mesoscopic structures that can be highly symmetric as capsid viruses or disordered molecular condensates exhibit a one-dimensional fibrillar morphology amyloid fibrils. Deposits latter tissues individuals with degenerative diseases like Alzheimer's and Parkinson's has motivated extensive efforts to understand sequence events their formation. These studies aim identify on-pathway intermediates may targets therapeutic intervention. This detailed knowledge fibril remains obscure, part due challenges experimental analyses these processes. However, progress is being achieved short peptides advances our ability perform completely unbiased all-atom simulations process. perspective discusses recent developments, implications, hurdles still need overcome further advance field.

Language: Английский

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Big versus small: The impact of aggregate size in disease

Protein Science, Journal Year: 2023, Volume and Issue: 32(7)

Published: May 27, 2023

Protein aggregation results in an array of different size soluble oligomers and larger insoluble fibrils. Insoluble fibrils were originally thought to cause neuronal cell deaths neurodegenerative diseases due their prevalence tissue samples disease models. Despite recent studies demonstrating the toxicity associated with oligomers, many therapeutic strategies still focus on or consider all types aggregates as one group. Oligomers require modeling strategies, targeting toxic species is crucial for successful study development. Here, we review role different-size disease, how factors contributing (mutations, metals, post-translational modifications, lipid interactions) may promote opposed We two computational (molecular dynamics kinetic modeling) they are used model both Finally, outline current aggregating proteins strengths weaknesses versus Altogether, aim highlight importance distinguishing difference between determining which when creating therapeutics protein disease.

Language: Английский

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Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells

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

Published: March 27, 2024

Abstract Misfolded soluble trimeric species of superoxide dismutase 1 (SOD1) are associated with increased death in neuron-like cell models and greater disease severity amyotrophic lateral sclerosis (ALS) patients compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may be a driver pathology. Here, we uncovered the trimer interactome – map potential tissue-selective binding partners brain, spinal cord, skeletal muscle. We identified key pathways trimers, comparing them those wild-type dimers. found that affect normal functions such as dendritic spine morphogenesis synaptic function central nervous system metabolism also using transcriptomic data from motor cells (NSC-34s) expressing trimers. discovered differential gene expression express selective enrichment genes responsible for localization membranes global upregulation senescence pathways. performed detailed computational biochemical characterization septin-7, an partner. septin-7 preferentially binds co-localizes cells. explore double-edged sword theory regarding These implicated causing dysfunction not only muscle tissues. Our investigation highlights factors within each system, revealing plausible intersection genetic pathophysiological mechanisms ALS through interactions involving Summary In (ALS), misfolded and, specifically, forms toxic role unknown. Using molecular engineering pull-down experiments, have nerves, energy, amino acid investigated transcriptome reveal further validated shared brain cord hit, integrative approaches, confirmed native Taken together, show evidence play convergence pathophysiology. Graphical abstract

Language: Английский

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Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells

Structure, Journal Year: 2024, Volume and Issue: 32(10), P. 1776 - 1792.e5

Published: Aug. 28, 2024

Language: Английский

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