α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies

Neurology, Journal Year: 2022, Volume and Issue: 99(5), P. 195 - 205

Published: June 3, 2022

Parkinson disease (PD) is the second most common neurodegenerative disease, and synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset progression. Although neuropathologic changes begin many years before of motor manifestations, diagnosis still relies on identification symptoms, which hinders to formulate early diagnosis. Because α-syn misfolding aggregation precede clinical possibility identify these phenomena patients with PD would allow us recognize at earliest, premotor phases, consequence transition from molecular Seed amplification assays (SAAs) are group techniques that currently support prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These enable detection minimal amounts prions CSF other matrices affected patients. Recently, SAAs have been successfully applied detect misfolded (α-syn) CSF, olfactory mucosa, submandibular gland biopsies, skin, saliva synucleinopathies. In categories, they can differentiate dementia Lewy bodies (DLBs) control subjects, even prodromal stages differential diagnosis, satisfactorily differentiated PD, DLB, multiple system atrophy (MSA) nonsynucleinopathy parkinsonisms. The kinetic analysis SAA fluorescence profiles allowed synucleinopathy-dependent fibrils conformations, commonly referred strains, demonstrated diagnostic potential differentiating among synucleinopathies, especially between body diseases (LBDs) (PD DLB) MSA. front highly promising data, make seeding activity detected by biomarker for there preanalytical analytical issues, mostly related assay standardization, need be solved. this review, we discuss key findings supporting application unmet needs, future perspectives.

Language: Английский

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Autophagy in health and disease: From molecular mechanisms to therapeutic target

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: July 10, 2022

Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over past two decades, autophagy has been extensively studied, from molecular mechanisms, biological functions, implications various human diseases, development of autophagy-related therapeutics. This review will focus on latest research, covering mechanisms control biogenesis autophagosome-lysosome fusion, upstream regulatory pathways including AMPK MTORC1 pathways. We also provide a systematic discussion implication cancer, neurodegenerative disorders (Alzheimer disease, Parkinson Huntington's Amyotrophic lateral sclerosis), metabolic diseases (obesity diabetes), viral infection especially SARS-Cov-2 COVID-19, cardiovascular (cardiac ischemia/reperfusion cardiomyopathy), aging. Finally, we summarize pharmacological agents that have therapeutic potential clinical applications via targeting pathway. It believed decades hard work research eventually bring real tangible benefits improvement health diseases.

Language: Английский

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The Multiple Roles of Autophagy in Neural Function and Diseases

Neuroscience Bulletin, Journal Year: 2023, Volume and Issue: 40(3), P. 363 - 382

Published: Oct. 19, 2023

Abstract Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes, where proteins, lipids, organelles are degraded recycled. According way components engulfed, autophagy can be divided into macroautophagy, microautophagy, chaperone-mediated autophagy. Recently, many studies have found that plays an important role in neurological diseases, including Alzheimer's disease, Parkinson's Huntington's neuronal excitotoxicity, cerebral ischemia. maintains cell homeostasis nervous system via degradation misfolded elimination damaged organelles, regulation apoptosis inflammation. AMPK-mTOR, Beclin 1, TP53 , endoplasmic reticulum stress, other signal pathways involved used as potential therapeutic targets for diseases. Here, we discuss role, functions, which will shed light on pathogenic mechanisms diseases suggest novel therapies.

Language: Английский

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Neuropathogenesis-on-chips for neurodegenerative diseases

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

Published: March 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Language: Английский

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Emerging roles of SIRT1 activator, SRT2104, in disease treatment

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 6, 2024

Abstract Silent information regulator 1 (SIRT1) is a NAD + -dependent class III deacetylase that plays important roles in the pathogenesis of numerous diseases, positioning it as prime candidate for therapeutic intervention. Among its modulators, SRT2104 emerges most specific small molecule activator SIRT1, currently advancing into clinical translation phase. The primary objective this review to evaluate emerging SRT2104, and explore potential agent various diseases. In present review, we systematically summarized findings from an extensive array literature sources including progress application disease treatment molecular mechanisms by reviewing published databases such PubMed, Web Science, World Health Organization International Clinical Trials Registry Platform. We focuses on strides made employing treatment, elucidating underpinnings based preclinical research data. reveal potent SIRT1 activator, holds considerable potential, particularly modulating metabolic longevity-related pathways. This establishes leading with significant promise.

Language: Английский

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Identification of Cathepsin B as a Therapeutic Target for Ferroptosis of Macrophage after Spinal Cord Injury

Aging and Disease, Journal Year: 2024, Volume and Issue: 15(1), P. 421 - 421

Published: Jan. 1, 2024

Hemorrhage and immune cell infiltration are the main pathological features of spinal cord injury (SCI). Excessive iron deposition is caused by leaking hemosiderin which may over-activate ferroptosis pathways, resulting in lipid peroxidation mitochondrial dysfunction cells. Inhibiting after SCI has been shown to aid functional recovery. However, essential genes involved cellular following still unknown. Here we show that Ctsb a statistical significance gene collecting multiple transcriptomic profiles identifying differentially expressed ferroptosis-related genes, abundantly myeloid cells widely distributed at epicenter injury. The expression score ferroptosis, calculated driver/suppressor was high macrophages. Furthermore, discovered inhibiting cathepsin B (CTSB), specifically with small-molecule drug, CA-074-methyl ester (CA-074-me), reduced We also found alternatively activated M2-polarized macrophages more susceptible hemin-induced ferroptosis. Consequently, CA-074-me could reduce induce M2 macrophage polarization, promote neurological function recovery mice SCI. Our study comprehensively analyzed from perspective transcriptomes provided novel molecular target for treatment.

Language: Английский

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Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein

Acta Neuropathologica Communications, Journal Year: 2020, Volume and Issue: 8(1)

Published: Feb. 14, 2020

Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including substantia nigra pars compacta (SNpc), where marked loss dopaminergic neurons also observed. Yet, relationship between and neurotoxicity currently remains unclear. As principal route for degradation proteins mammalian cells, ubiquitin-proteasome system (UPS) critical maintenance cellular proteostasis. Misfolded impairs UPS function contributes to neuronal death vitro. Here, we examine its effects vivo using adeno-associated viruses co-express A53T ubiquitinated reporter protein Ub G76V -GFP rat SNpc. We found that over-expression leads early-onset catalytic impairment 26S proteasome with associated dysfunction, preceding onset behavioural deficits neurodegeneration. failure was selective phosphorylated at serine 129 residue, which has previously been linked increased neurotoxicity. Our study highlights role disturbing proteostasis may contribute neurodegeneration .

Language: Английский

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The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

Movement Disorders, Journal Year: 2020, Volume and Issue: 36(5), P. 1070 - 1085

Published: Nov. 21, 2020

ABSTRACT Parkinson's disease (PD) is a progressive neurodegenerative where dopaminergic neurons in the substantia nigra are lost, resulting decrease striatal dopamine and, consequently, motor control. Dopaminergic degeneration associated with appearance of Lewy bodies, which contain membrane structures and proteins, including α‐synuclein (α‐Syn), surviving neurons. PD displays multifactorial pathology develops from interactions between multiple elements, such as age, environmental conditions, genetics. Mutations GBA1 gene represent one major genetic risk factors for PD. This encodes an essential lysosomal enzyme called β‐glucocerebrosidase (GCase), responsible degrading glycolipid glucocerebroside into glucose ceramide. GCase can generate glucosylated cholesterol via transglucosylation also degrade sterol glucoside. Although molecular mechanisms that predispose individual to neurodegeneration remain unknown, role deserves consideration. Disturbed cellular metabolism, reflected by accumulation ‐associated models, could contribute changes lipid rafts, necessary synaptic localization vesicle cycling modulation integrity. α‐Syn has been implicated regulation neuronal cholesterol, facilitates oligomers. In this review, we integrate results previous studies describe landscape homeostasis function. We discuss its implication body pathophysiological underlying PD, focusing on cholesterol. © 2020 The Authors. Movement Disorders published Wiley Periodicals LLC behalf International Parkinson Disorder Society

Language: Английский

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Long Noncoding RNA POU3F3 and α-Synuclein in Plasma L1CAM Exosomes Combined with β-Glucocerebrosidase Activity: Potential Predictors of Parkinson's Disease

Neurotherapeutics, Journal Year: 2020, Volume and Issue: 17(3), P. 1104 - 1119

Published: March 31, 2020

Language: Английский

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CSF and Blood Biomarkers in Neuroinflammatory and Neurodegenerative Diseases: Implications for Treatment

Trends in Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 41(12), P. 1023 - 1037

Published: Oct. 27, 2020

Language: Английский

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