Cellular functions of the protein kinase ATM and their relevance to human disease

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 22(12), С. 796 - 814

Опубликована: Авг. 24, 2021

Язык: Английский

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Interpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Май 15, 2019

Abstract Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline that identifies specific neuropathologies—amyloid plaques cerebral amyloid angiopathy—in immunohistochemically-stained archival slides. Using automated segmentation of stained objects cloud-based interface, we annotate > 70,000 plaque candidates from 43 whole slide images (WSIs) train evaluate convolutional neural networks. Networks achieve strong classification on 10-WSI hold-out set (0.993 0.743 under the receiver operating characteristic precision recall curve, respectively). Prediction confidence maps visualize morphology distributions at high resolution. Resulting network-derived beta (Aβ)-burden scores correlate well with established 30-WSI blinded hold-out. Finally, saliency mapping demonstrates networks learn patterns agreeing accepted pathologic features. This scalable means augment neuropathologist’s ability suggests route neuropathologic phenotyping.

Язык: Английский

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Tauopathies: new perspectives and challenges

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Апрель 7, 2022

Abstract Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with range phenotypes that include cognitive/behavioral-disorders, movement disorders, language and non-specific amnestic symptoms in advanced age. Pathologically, be classified based on the predominant tau isoforms inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) blood-based biomarkers have potential to used as routine diagnostic strategy evaluation patients tauopathies. As strongly linked neuropathologically genetically protein abnormalities, there is growing interest pursuing tau-directed therapeutics for disorders. Here we synthesize emerging lessons from clinical, pathological, genetic, experimental studies toward unified concept these may accelerate therapeutics. Conclusions Since still untreatable diseases, efforts been made depict clinical pathological characteristics, identify biomarkers, elucidate underlying pathogenesis achieve early diagnosis develop disease-modifying therapies.

Язык: Английский

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Antioxidant and Anti-Inflammatory Effects of Citrus Flavonoid Hesperetin: Special Focus on Neurological Disorders

Antioxidants, Год журнала: 2020, Номер 9(7), С. 609 - 609

Опубликована: Июль 10, 2020

Neurodegenerative disorders have emerged as a serious health issue in the current era. The most common neurodegenerative are Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). These diseases involve progressive impairment of neurodegeneration memory impairment. A wide range compounds been identified potential neuroprotective agents against different models both vivo vitro. Hesperetin, flavanone class citrus flavonoid, is derivative hesperidin found fruits such oranges, grapes, lemons. It has extensively reported that hesperetin exerts effects experimental diseases. In this systematic review, we compiled all studies conducted on vitro neurodegeneration. Here, used an approach to lessen bias each study, providing least biased, broad understanding findings impartial conclusions strength evidence reliability findings. collected papers from journals describing beneficial animal Our results demonstrated consistent addition, summarized its underlying mechanisms. This study provides foundations for future recommendations further mechanistic approaches conduct preclinical models.

Язык: Английский

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The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis

Advances in experimental medicine and biology, Год журнала: 2021, Номер unknown, С. 41 - 57

Опубликована: Янв. 1, 2021

Язык: Английский

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Effects of curcumin on mitochondria in neurodegenerative diseases

BioFactors, Год журнала: 2019, Номер 46(1), С. 5 - 20

Опубликована: Окт. 3, 2019

Abstract Neurodegenerative diseases (NDs) result from progressive deterioration of selectively susceptible neuron populations in different central nervous system (CNS) regions. NDs are classified accordance with the primary clinical manifestations (e.g., parkinsonism, dementia, or motor disease), anatomic basis neurodegeneration frontotemporal degenerations, extrapyramidal disorders, spinocerebellar degenerations), and fundamental molecular abnormalities mutations, mitochondrial dysfunction, its related alterations). include Alzheimer disease Parkinson disease, among others. There is a growing evidence that dysfunction mutations form oxidative/nitrosative stress neurotoxic compounds play major roles pathogenesis various NDs. Curcumin, polyphenol nontoxic compound, obtained turmeric, has been shown to have therapeutic beneficial effect disorders especially on CNS cells. It curcumin considerable neuro‐ mitochondria‐protective properties against broad‐spectrum diseases/injury‐associating In this article, we reviewed effects

Язык: Английский

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Roles of XBP1s in Transcriptional Regulation of Target Genes

Biomedicines, Год журнала: 2021, Номер 9(7), С. 791 - 791

Опубликована: Июль 8, 2021

The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA cleaved by activated stress sensor IRE1α and converted to mature encoding XBP1 (XBP1s). Translated XBP1s migrates nucleus regulates transcriptional programs UPR target genes ER molecular chaperones, folding enzymes, ER-associated degradation (ERAD) components decrease stress. Moreover, studies have shown diverse are involved lipid glucose metabolism immune responses. Therefore, has been considered important therapeutic studying various diseases, including cancer, diabetes, autoimmune inflammatory diseases. several unique mechanisms regulate different interacting with other proteins modulate their activity. Although recent discovered numerous via genome-wide analyses, how remains unclear. This review discusses roles regulation. More in-depth knowledge regulatory future will help develop new targets for each disease.

Язык: Английский

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Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases

Progress in Neurobiology, Год журнала: 2022, Номер 214, С. 102270 - 102270

Опубликована: Апрель 18, 2022

Aggregation of specific proteins are histopathological hallmarks several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions ratiometric 3 repeat (3 R) 4 (4 isoforms progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) dystrophic neurites (LNs) Parkinson's (PD) dementia with (DLB). However, mixed brain protein pathologies have been frequently observed many these diseases normal aging brains, among which Aβ/tau tau/α-Syn crosstalks received increased attention. Interestingly, studies also shown synergistic interplay Aβ, tau, α-Syn suggesting a triumvirate. In this review, we summarize the emerging evidence aggregation pathophysiology, their overlap spectrum including AD, PSP, PiD, CBD, PD DLB. We discuss prognostic advancements made biomarker imaging techniques triumvirate proteinopathies. Finally, combined therapeutic modality involving biomarkers for future combinatorial immunotherapeutic targeting more than one aggregates. hope that multitarget approach will or additive effects to manage two might uncover promising strategy personalized combination therapies. Managing by optimizing diagnostic criteria correct immunotherapies be key factor success treatment.

Язык: Английский

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Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Cell, Год журнала: 2019, Номер 178(3), С. 521 - 535.e23

Опубликована: Июль 1, 2019

Язык: Английский

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Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases

Ageing Research Reviews, Год журнала: 2020, Номер 65, С. 101202 - 101202

Опубликована: Ноя. 5, 2020

Язык: Английский

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