Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

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Modulation of cellular processes by histone and non-histone protein acetylation

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(5), P. 329 - 349

Published: Jan. 18, 2022

Language: Английский

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Protein transmission in neurodegenerative disease

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(4), P. 199 - 212

Published: March 23, 2020

Language: Английский

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Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(8), P. 1256 - 1263

Published: June 22, 2020

Language: Английский

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A current view on Tau protein phosphorylation in Alzheimer's disease

Current Opinion in Neurobiology, Journal Year: 2021, Volume and Issue: 69, P. 131 - 138

Published: April 21, 2021

The functions of the neuronal microtubule-associated protein Tau in central nervous system are regulated by manifold posttranslational modifications at more than 50 sites. healthy neurons carries multiple phosphate groups, mostly its microtubule assembly domain. Elevated phosphorylation and aggregation widely considered pathological hallmarks Alzheimer's disease (AD) other tauopathies, triggering quest for context. However, patterns physiological surprisingly similar heterogenous, making it difficult to identify specific as therapeutic targets biomarkers AD. We present a concise summary - view on important previous recent advances analysis context

Language: Английский

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The expanding amyloid family: Structure, stability, function, and pathogenesis

Cell, Journal Year: 2021, Volume and Issue: 184(19), P. 4857 - 4873

Published: Sept. 1, 2021

Language: Английский

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The emerging mechanisms and functions of microautophagy

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 186 - 203

Published: Sept. 12, 2022

Language: Английский

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Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 7, 2021

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information potential observed PTMs provides an opportunity better understand these in the context homeostasis, which becomes perturbed with aging disease. Prevailing views regard a that undergoes abnormal phosphorylation prior its accumulation into toxic aggregates implicated Alzheimer's disease (AD) other tauopathies. However, may, fact, represent part normal but interrupted catabolism protein. In addition phosphorylation, another forms post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, nitration. A holistic appreciation how regulate during health are potentially hijacked remains elusive. Recent studies reinforced idea play critical role localization, protein-protein interactions, maintenance levels, modifying aggregate structure. These also provide tantalizing clues possibility neurons actively choose is post-translationally modified, competitive combinatorial ways, achieve broad, cellular programs commensurate distinctive environmental conditions found development, aging, stress, Here, we review describe what currently known about their functional impacts. addition, classify from perspectives electrostatics, stability, all contribute homeostasis. Finally, assess impact solubility aggregation. Tau occupies undoubtedly important position biology neurodegenerative diseases. This aims integrated perspective actively, purposefully, dynamically remodel function, clearance, doing so, hope enable more comprehensive understanding will positively future studies.

Language: Английский

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Hydrogen sulfide is neuroprotective in Alzheimer’s disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(4)

Published: Jan. 11, 2021

Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in elderly, is characterized by deterioration memory executive motor functions. Neuropathologic hallmarks AD include neurofibrillary tangles (NFTs), paired helical filaments, amyloid plaques. Mutations microtubule-associated protein Tau, a major component NFTs, its hyperphosphorylation AD. We have shown that signaling gaseous molecule hydrogen sulfide (H2S) dysregulated during aging. H2S signals via posttranslational modification termed sulfhydration/persulfidation, which participates diverse cellular processes. Here we show cystathionine γ-lyase (CSE), biosynthetic enzyme for H2S, binds wild type enhances catalytic activity. By contrast, CSE fails to bind Tau P301L, mutant present 3xTg-AD mouse model further depleted mice as well human brains, prevents sulfhydrating kinase, glycogen synthase kinase 3β (GSK3β). Finally, demonstrate sulfhydration diminished AD, while administering donor sodium GYY4137 (NaGYY) ameliorates cognitive deficits

Language: Английский

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Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Aug. 12, 2021

Mass spectrometry-based proteomics empowers deep profiling of proteome and protein posttranslational modifications (PTMs) in Alzheimer's disease (AD). Here we review the advances limitations historic recent AD proteomic research. Complementary to genetic mapping, studies not only validate canonical amyloid tau pathways, but also uncover novel components broad networks, such as RNA splicing, development, immunity, membrane transport, lipid metabolism, synaptic function, mitochondrial activity. Meta-analysis seven datasets reveals 2,698 differentially expressed (DE) proteins landscape brain (n = 12,017 proteins/genes), covering 35 reported genes risk loci. The DE contain cellular markers enriched neurons, microglia, astrocytes, oligodendrocytes, epithelial cells, supporting involvement diverse cell types pathology. We discuss hypothesized protective or detrimental roles selected proteins, emphasizing top "amyloidome" (all biomolecules plaques) progression. Comprehensive PTM analysis represents another layer molecular events AD. In particular, PTMs are correlated with stages indicate heterogeneity individual patients. Moreover, unprecedented coverage biofluids, cerebrospinal fluid serum, procures putative biomarkers through meta-analysis. Thus, proteomics-driven systems biology presents a new frontier link genotype, proteotype, phenotype, accelerating development improved models treatment strategies.

Language: Английский

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