Leveraging a large language model to predict protein phase transition: A physical, multiscale, and interpretable approach DOI Creative Commons
Mor Frank, Pengyu Ni, Matthew L. Jensen

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(33)

Published: Aug. 7, 2024

Protein phase transitions (PPTs) from the soluble state to a dense liquid (forming droplets via liquid–liquid separation) or solid aggregates (such as amyloids) play key roles in pathological processes associated with age-related diseases such Alzheimer’s disease. Several computational frameworks are capable of separately predicting formation amyloid based on protein sequences, yet none have tackled prediction both within unified framework. Recently, large language models (LLMs) exhibited great success structure prediction; however, they not been used for PPTs. Here, we fine-tune LLM PPTs and demonstrate its usage evaluating how sequence variants affect PPTs, an operation useful design. In addition, show superior performance compared suitable classical benchmarks. Due “black-box” nature LLM, also employ random forest model along biophysical features facilitate interpretation. Finally, focusing disease-related proteins, that greater aggregation is reduced gene expression disease, suggesting natural defense mechanism.

Language: Английский

Advances in Alzheimer's disease: A multifaceted review of potential therapies and diagnostic techniques for early detection DOI
Monika Sharma, Pankaj Pal, Sukesh Kumar Gupta

et al.

Neurochemistry International, Journal Year: 2024, Volume and Issue: 177, P. 105761 - 105761

Published: May 7, 2024

Language: Английский

Citations

15
The Promise of Niacin in Neurology DOI Creative Commons
Emily Wuerch, Gloria Roldan Urgoiti, V. Wee Yong

et al.

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 20(4), P. 1037 - 1054

Published: April 21, 2023

Language: Английский

Citations

30
Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry DOI Creative Commons
Thomas Grewal,

Mai Khanh Linh Nguyen,

Christa Buechler

et al.

Life Science Alliance, Journal Year: 2024, Volume and Issue: 7(5), P. e202302453 - e202302453

Published: Feb. 22, 2024

The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical reduce the severity COVID-19. However, continuous emergence new SARS-CoV-2 subtypes highlights need develop additional approaches that oppose viral infections. Targeting host factors support virus entry, replication, and propagation provide opportunities lower infection rates improve COVID-19 outcome. This includes cellular cholesterol, which is for spike proteins capture machinery cell entry. Once endocytosed, exit from late endosomal/lysosomal compartment occurs in a cholesterol-sensitive manner. In addition, effective release particles also requires cholesterol. Hence, cholesterol-lowering statins, proprotein convertase subtilisin/kexin type 9 antibodies, ezetimibe have revealed potential protect against pharmacological inhibition cholesterol exiting endosomes/lysosomes identified drug candidates, including antifungals, block infection. review describes multiple roles at surface endolysosomes entry drugs targeting homeostasis infectivity disease severity.

Language: Английский

Citations

9
Cholesterol imbalance and neurotransmission defects in neurodegeneration DOI Creative Commons
Kyung Chul Shin,

Houda Yasmine Ali Moussa,

Yongsoo Park

et al.

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(8), P. 1685 - 1690

Published: Aug. 1, 2024

The brain contains the highest concentration of cholesterol in human body, which emphasizes importance physiology. Cholesterol is involved neurogenesis and synaptogenesis, age-related reductions levels can lead to synaptic loss impaired plasticity, potentially contribute neurodegeneration. maintenance homeostasis neuronal plasma membrane essential for normal function, imbalances distribution are associated with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's Huntington's disease. This review aims explore molecular pathological mechanisms by imbalance neurotransmission defects neurodegeneration, focusing on four key mechanisms: (1) dysfunction, (2) alterations structure protein clustering, (3) oligomers amyloid beta (Aβ) protein, (4) α-synuclein aggregation.

Language: Английский

Citations

9
Neurosteroid enantiomers as potentially novel neurotherapeutics DOI Creative Commons
Douglas F. Covey, Alex S. Evers, Yukitoshi Izumi

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105191 - 105191

Published: April 20, 2023

Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These modulate major signaling systems the brain intracellular processes including inflammation, cellular stress autophagy. In this review, we describe studies performed using unnatural enantiomers of key neurosteroids, which physiochemically identical to their natural counterparts except rotation polarized light. led insights how NAS interact with receptors, ion channels sites action. Certain effects show high enantioselectivity, consistent actions chiral environments likely direct interactions proteins. Other no enantioselectivity even reverse enantioselectivity. The spectrum raises possibility that these agents, once considered only as tools preclinical studies, have potential complements some cases may exceed counterparts. Here review from perspective novel neurotherapeutics.

Language: Английский

Citations

19
Effect of the Lipid Landscape on the Efficacy of Cell-Penetrating Peptides DOI Creative Commons
Florina Zákány, István M. Mándity, Zoltán Varga

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(13), P. 1700 - 1700

Published: June 23, 2023

Every cell biological textbook teaches us that the main role of plasma membrane is to separate cells from their neighborhood allow for a controlled composition intracellular space. The mostly hydrophobic nature presents an impenetrable barrier most hydrophilic molecules larger than 1 kDa. On other hand, cell-penetrating peptides (CPPs) are capable traversing this without compromising integrity, and they can do so on own or coupled cargos. Coupling biologically medically relevant cargos CPPs holds great promise delivering membrane-impermeable drugs into cells. If cargo able interact with certain types, uptake CPP–drug complex be tailored cell-type-specific. Besides outlining major penetration pathways CPPs, review aimed at deciphering how properties influence mechanisms CPPs. By summarizing extensive body experimental evidence, we argue more ordered, less flexible structure, often present in very diseases planned treated decreases cellular uptake. These correlations not only understanding biology but also rationally improving value translational clinical applications.

Language: Английский

Citations

18
White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review DOI Creative Commons
Frank R. Sharp, Charles DeCarli,

Lee‐Way Jin

et al.

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

Published: Feb. 10, 2023

We postulate that myelin injury contributes to cholesterol release from and dysmetabolism which Abeta dysmetabolism, combined with genetic AD risk factors, leads increased amyloid plaques. Increased damages form a vicious cycle. Thus, white matter injury, interact produce or worsen neuropathology. The cascade is the leading hypothesis for cause of Alzheimer’s disease (AD). failure clinical trials based on this has raised other possibilities. Even possible new success (Lecanemab), it not clear whether result disease. With discovery in 1993 apolipoprotein E type 4 allele (APOE4) was major factor sporadic, late-onset (LOAD), there been increasing interest since APOE transporter. Recent studies show metabolism intricately involved (Aβ)/amyloid transport metabolism, down-regulating Aβ LRP1 transporter upregulating RAGE receptor, both would increase brain Aβ. Moreover, manipulating rodent models can ameliorate pathology cognitive deficits, them depending upon manipulation. Though (WM) noted initial observations, recent have shown abnormal every brain. age-related WM normal individuals occurs earlier worse APOE4 genotype. precedes formation plaques tangles human Familial (FAD) plaque models. Restoring improves cognition without affecting pathology. we cascade, and/or further primary initiating event could be related any three, age diet genes FAD dysmetabolism.

Language: Английский

Citations

14
Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol DOI Creative Commons
Vladimı́r Rudajev, Jiřı́ Novotný

Cell & Bioscience, Journal Year: 2023, Volume and Issue: 13(1)

Published: Sept. 13, 2023

Abstract Amyloid β is considered a key player in the development and progression of Alzheimer’s disease (AD). Many studies investigating effect statins on lowering cholesterol suggest that there may be link between levels AD pathology. Since one most abundant lipid molecules, especially brain tissue, it affects membrane-related processes, including formation dangerous form amyloid β, Aβ42. The entire Aβ production system, which includes precursor protein (APP), β-secretase, complex γ-secretase, highly dependent membrane content. Moreover, can affect amyloidogenesis many ways. Cholesterol influences stability activity secretases, but also dictates their partitioning into specific cellular compartments cholesterol-enriched rafts, where amyloidogenic machinery predominantly localized. complicated relationships have been found interaction APP, not only APP localization precise character dimerization processing by important for different lengths . In this review, we describe intricate web interdependence levels, distribution, cholesterol-dependent Aβ, major AD.

Language: Английский

Citations

13
Modulation of cholesterol metabolism with Phytoremedies in Alzheimer’s disease: A comprehensive review DOI
Sushruta Koppula, Nitu L. Wankhede, Shivkumar S. Sammeta

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 99, P. 102389 - 102389

Published: June 19, 2024

Language: Английский

Citations

5
Pten Loss Triggers Progressive Photoreceptor Degeneration in an mTORC1-Independent Manner DOI Creative Commons

Joseph Hanna,

Yacine Touahri,

Alissa Pak

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2025, Volume and Issue: 66(3), P. 45 - 45

Published: March 21, 2025

Purpose: Silencing Phosphatase and tensin homolog (Pten) is a proposed therapeutic strategy for tissue regeneration to treat neurological disorders. However, Pten pleiotropic, inhibiting several signaling metabolic pathways, including mTORC1 glycolysis, both pro-regenerative in certain contexts. This study aims assess the long-term impact of inactivating on photoreceptor survival retina identify downstream pathway(s). Methods: We assessed retinal integrity conditional knock-outs (cKOs) that were progenitor cell (RPC)-specific (Pten RPC-cKO), congenital model, or rod-specific Rho-cKO). examined early changes gene expression used immunostaining photoreceptors, reactive astrocytes, microglia, angiogenesis, subretinal deposit formation from postnatal day (P) 21 1 year age. RPC-cKO explants treated with rapamycin, an mTOR inhibitor, 2-deoxy-D-glucose (2DG), glycolysis inhibitor. Results: In Pten-cKO models, retinas display signs pathogenesis as photoreceptor-specific downregulated at P0, before loss. loss triggers progressive rod cone degeneration beginning P21 RPC-cKOs 6 months age Rho-cKOs. Activated microglia increased are observed while amyloid-β deposits develop RPC-cKOs. Rapamycin accelerates RPC-cKOs, whereas 2DG has no effect. Conclusions: Our findings suggest loss, either RPCs solely mature leads exacerbated by suppression, drawing into question value Pten-mTORC1 manipulations.

Language: Английский

Citations

0