Massively parallel screening of TIR-derived peptides reveals vast TLR-targeting immunomodulatory peptides DOI Creative Commons
Yun Lim,

Tae Kyeom Kang,

Meong Il Kim

et al.

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

Published: May 22, 2024

Abstract Toll-like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety inflammatory diseases. Interference intracellular signaling, which is mediated by multiple Toll/interleukin-1 receptor (TIR) domains on all TLRs adapters, an effective therapeutic strategy against dysregulation. Peptides that inhibit TIR-TIR interactions fragmenting interface residues have potential as decoys. However, systematic method for discovering TIR-targeting moieties has been elusive, limiting exploration vast unsequenced space TIR domain family. Here, we developed comprehensive parallel screening uncover novel TIR-binding peptides derived from previously unexplored surfaces wide range domains. We constructed large peptide library, named surfacesome, tiling surface sequences family MAL MyD88 , TIRs two major adaptor proteins, resulting in discovery hundreds peptides. The selected inhibited demonstrated anti-inflammatory effects macrophages mouse models. This approach may facilitate development TLR-targeted therapeutics.

Language: Английский

Molecular de-extinction of ancient antimicrobial peptides enabled by machine learning DOI
Jacqueline R. M. A. Maasch, Marcelo D. T. Torres, Marcelo C. R. Melo

et al.

Cell Host & Microbe, Journal Year: 2023, Volume and Issue: 31(8), P. 1260 - 1274.e6

Published: July 28, 2023

Language: Английский

Citations

84
Deep-learning-enabled antibiotic discovery through molecular de-extinction DOI Creative Commons
Fangping Wan, Marcelo D. T. Torres, Jacqueline Peng

et al.

Nature Biomedical Engineering, Journal Year: 2024, Volume and Issue: 8(7), P. 854 - 871

Published: June 11, 2024

Molecular de-extinction aims at resurrecting molecules to solve antibiotic resistance and other present-day biological biomedical problems. Here we show that deep learning can be used mine the proteomes of all available extinct organisms for discovery peptides. We trained ensembles deep-learning models consisting a peptide-sequence encoder coupled with neural networks prediction antimicrobial activity it 10,311,899 The predicted 37,176 sequences broad-spectrum activity, 11,035 which were not found in extant organisms. synthesized 69 peptides experimentally confirmed their against bacterial pathogens. Most killed bacteria by depolarizing cytoplasmic membrane, contrary known peptides, tend target outer membrane. Notably, lead compounds (including mammuthusin-2 from woolly mammoth, elephasin-2 straight-tusked elephant, hydrodamin-1 ancient sea cow, mylodonin-2 giant sloth megalocerin-1 elk) showed anti-infective mice skin abscess or thigh infections. aided may accelerate therapeutic molecules.

Language: Английский

Citations

54
Key genes and convergent pathogenic mechanisms in Parkinson disease DOI
Robert Coukos, Dimitri Krainc

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(6), P. 393 - 413

Published: April 10, 2024

Language: Английский

Citations

32
Nuclear pore dysfunction and disease: a complex opportunity DOI Creative Commons
Charlotte M. Fare, Jeffrey D. Rothstein

Nucleus, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 21, 2024

The separation of genetic material from bulk cytoplasm has enabled the evolution increasingly complex organisms, allowing for development sophisticated forms life. However, this complexity created new categories dysfunction, including those related to movement between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions nuclear integrity transport are detrimental cell survival. This particularly true in post-mitotic neurons, where pore injury errors strongly associated with neurodegenerative disease. review, we summarize current understanding biology physiological pathological contexts discuss potential therapeutic approaches addressing dysfunctional transport.

Language: Английский

Citations

11
Current trends in basic research on Parkinson’s disease: from mitochondria, lysosome to α-synuclein DOI Creative Commons
Hideaki Matsui, Ryōsuke Takahashi

Journal of Neural Transmission, Journal Year: 2024, Volume and Issue: 131(6), P. 663 - 674

Published: April 13, 2024

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and other brain regions. A key pathological feature PD abnormal accumulation α-synuclein protein within affected neurons, manifesting as Lewy bodies neurites. Despite extensive research efforts spanning several decades, underlying mechanisms disease-modifying therapies remain elusive. This review provides an overview current trends basic on PD. Initially, it discusses involvement mitochondrial dysfunction pathogenesis PD, followed insights into role lysosomal disruptions vesicular transport system. Additionally, delves physiological roles α-synuclein, crucial associated with pathophysiology. Overall, purpose this to comprehend state elucidating intricate outline future directions understanding disease.

Language: Английский

Citations

9
Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure DOI
Munishwar N. Gupta, Vladimir N. Uversky

Protein Science, Journal Year: 2024, Volume and Issue: 33(4)

Published: March 27, 2024

Abstract The rationale for replacing the old binary of structure–function with trinity structure, disorder, and function has gained considerable ground in recent years. A continuum model based on expanded form existing paradigm can now subsume importance both conformational flexibility intrinsic disorder protein function. is actually critical understanding protein–protein interactions many regulatory processes, formation membrane‐less organelles, our revised notions specificity as amply illustrated by moonlighting proteins. While its amyloids prions often discussed, roles infectious diseases under extreme conditions are also becoming clear. This review an attempt to discuss how current function, specificity, evolution fit better model. integration structure a single may bring greater clarity continuing quest proteins molecular mechanisms their functionality.

Language: Английский

Citations

8
Vascular Impairment, Muscle Atrophy, and Cognitive Decline: Critical Age-Related Conditions DOI Creative Commons

Enzo Pereira de Lima,

Masaru Tanaka,

Caroline Barbalho Lamas

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(9), P. 2096 - 2096

Published: Sept. 13, 2024

The triad of vascular impairment, muscle atrophy, and cognitive decline represents critical age-related conditions that significantly impact health. Vascular impairment disrupts blood flow, precipitating the mass reduction seen in sarcopenia neuronal function characteristic neurodegeneration. Our limited understanding intricate relationships within this hinders accurate diagnosis effective treatment strategies. This review analyzes interrelated mechanisms contribute to these conditions, with a specific focus on oxidative stress, chronic inflammation, impaired nutrient delivery. aim is understand common pathways involved suggest comprehensive therapeutic approaches. dysfunctions hinder circulation transportation nutrients, resulting characterized by atrophy weakness. dysfunction have negative physical quality life. Neurodegenerative diseases exhibit comparable pathophysiological affect motor functions. Preventive approaches encompass lifestyle adjustments, addressing integrated therapies improving muscular well-being. Better links can refine strategies yield better patient outcomes. study emphasizes complex interplay between dysfunction, degeneration, decline, highlighting necessity for multidisciplinary Advances domain promise improved diagnostic accuracy, more options, enhanced preventive measures, all contributing higher life elderly population.

Language: Английский

Citations

8
Peptide-based approaches to directly target alpha-synuclein in Parkinson’s disease DOI Creative Commons

Scott G. Allen,

Richard M. Meade,

Lucy L. White Stenner

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Nov. 9, 2023

Abstract Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large inhibition by small inaccessible to larger biologics. In the past two decades, evidence associating misfolding aggregation of alpha-synuclein strongly implicates this protein in disease onset progression Parkinson’s related synucleinopathies. The subsequent formation toxic, intracellular, Lewy body deposits, which is a major component, key diagnostic hallmark disease. To reach therapeutic site action, peptides must both cross blood-brain barrier enter dopaminergic neurons prevent these inclusions. review, we describe summarise current efforts made development directly engage with intention modulating aggregation, importantly, toxicity. This rapidly expanding field great socioeconomic impact; molecules harbour significant promise therapeutics, or early biomarkers during prodromal stages, both. As age-dependent conditions, an increasing global life expectancy means prevalence rising. No treatments exist either slow progression. It therefore crucial that drugs developed conditions before health care social capacities become overrun.

Language: Английский

Citations

16
Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein DOI Creative Commons
Sarah Hui, Jimmy George, Minesh Kapadia

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(11), P. 9032 - 9042

Published: April 6, 2024

Abstract Parkinson’s disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to aggregation-prone protein α-synuclein. Accumulation of α-synuclein implicated in mitochondrial dysfunction and disruption autophagic turnover mitochondria, or mitophagy, which an essential quality control mechanism proposed preserve fidelity response aging stress. Yet, precise relationship between accumulation, autophagy, loss remains unresolved. Here, we determine kinetics overexpression mitophagy using pH-sensitive fluorescent mito-QC reporter. We find that mutant A53T either human SH-SY5Y cells rat primary cortical neurons induces mitophagy. Moreover, accumulation SNpc rats results dysregulation precedes onset neurodegeneration. This study reveals role for inducing dysfunction, may be early event contributing

Language: Английский

Citations

3
Amylin is incorporated into extracellular vesicles in an ESCRT-dependent manner and regulates senescence DOI

Sarai Iglesias-Fortes,

A. P. M. Lockwood,

Carlos González-Blanco

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 167699 - 167699

Published: Jan. 1, 2025

Language: Английский

Citations

0