α-Synuclein acts as a cholesteryl-ester sensor on lipid droplets regulating organelle size and abundance.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 20, 2024

Abstract While aggregated alpha-Synuclein (αSyn) is commonly associated with Parkinson’s disease, its physiological function as a membrane-binding protein poorly understood. Here, we show that endogenous αSyn binds lipid droplets (LDs) in multiple human cell lines and stem cell-derived dopaminergic neurons. LD-binding encompasses residues 1-100, which masks their detection by immunofluorescence microscopy, probably explaining the scarcity of similar observations earlier studies. αSyn-LD interactions are highly temperature-sensitive selective for cholesteryl-ester-rich LDs. They promote formation multimers dissociate from LDs at non-permissive temperatures. remains LD-bound throughout starvation-induced lipolysis, whereas siRNA-knockdown diminishes LD abundance compromises viability upon nutrient depletion, without affecting biosynthesis. Reciprocally, excess stimulates accumulation dependence availability, restricts organelle size ensures intracellular organization, strictly depends on functional membrane-binding. Supporting general role cellular cholesterol metabolism, our results point to additional loss-of-function similarities between Parkinson’s, Alzheimer’s Gaucher’s disease.

Язык: Английский

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Brain cholesterol therapy for Huntington's disease – Does it make sense?

Clinical and Translational Medicine, Год журнала: 2024, Номер 14(7)

Опубликована: Июнь 25, 2024

The use of cholesterol as a therapy for Huntington's disease (HD) might seem peculiar at first, but it has strong experimental foundation. HD, like other chronic neurodegenerative disorders, lacks disease-modifying therapies and limited symptomatic treatments the movement psychiatric problems that characterise it. additional abnormal sleep patterns weight loss are managed with supportive approaches. These disturbances arise from CAG expansion in huntingtin gene, leading to dysfunction death neurons cortex striatum. process likely begins years before clinical presentation. Work is ongoing identify earliest pathology stages using imaging, biomarker measures.1 One-fifth all human body brain, where crucial neuronal function membrane integrity. blood–brain barrier (BBB) prevents uptake lipoprotein-bound systemic circulation; thus, brain originates local synthesis, primarily astrocytes, through multistep pathway involving several enzymes. Neurons have biosynthesis capabilities rely on astrocytes their supply, so protect them potentially harmful effects excessive production. Over last 25 years, work Cattaneo lab demonstrated across wide variety models severely reduced HD brain.2 A meta-analysis cognitive data studies mice exposed cholesterol-increasing strategies also showed that, regardless approach type, delivery system, mouse genotype time administration, performance treated greatly improved relative untreated groups.2, 3 As such, concept increasing levels or stimulating its well justified. Various been explored raise Direct infusion into 369 µg via an osmotic-minipump rescued both motor abnormalities, while 15 cognition only. gene forcing expression SREBP2 (the transcription factor promoting biosynthesis) again, leads rescue functions mice. Intraperitoneal injection cholesterol-loaded nanoparticles, modified cross BBB, was found be successful two models, providing long-lasting behavioural neuropathological benefits no side effects.3 Indeed, even giving ahead overt features slowed onset. More recently, intranasal shown great potential HD.2 trial restore patients AB-1001 started paused until 2025.4 Formerly known hCYP46A1, this converts approximately 6 mg per day hydrophilic catabolite, 24-hydroxycholesterol (24OHC), which then leaves detectable plasma. This designed Alzheimer's (AD), accumulates pathologically contributes aggregate formation, reverse situation seen. But what evidence changes brain? Measurements 24OHC plasma thus far yielded inconclusive results, longitudinal still awaited. recently developed PET tracer binds CYP46A1 will very informative, allow visualisation metabolism spatial resolution living brain.5 Studies investigating statins progression may they complicated by fact these drugs multiple actions target peripheral cholesterol, although many can pass BBB. Animal suggest should worsen HD. Initial humans show less severe statin-treated patients, unable distinguish between lowering lipid level underlying hyperlipidemia itself directly slowing down progression.6 At stage, strongest supporting comes animal studies. However, translating trials presents challenges, including lack intellectual property resistance drug. Optimal dosage, efficacy, biosafety GMP-grade administration needs investigation, does how best deliver brain. neither challenges insurmountable example, subcutaneous implantation minipumps already employed direct glioma Parkinson's Disease. Inorganic, organic (liposomal), hybrid nanoparticles used chemotherapeutic agents tumours.7 Intranasal another viable method trialled AD already.8 Moreover, assessing efficacy requires reliable biomarkers robust outcome measures. failure previous trials, such those antisense oligonucleotides, underscores importance having clinically relevant endpoints accurately reflect treatment response right site.9 Looking measures, assessments, neuroimaging, analyses blood/CSF markers neurofilament-light-chain, GFAP mutant huntingtin, offer more comprehensive evaluation therapeutic outcomes none ideal, combination measures useful approach.10 Finally, prolonged prodromal phase during dysfunctional not yet lost. Providing period help prolong synaptic functionality. trialling approaches premanifest raises number ethical (around safety essentially normal individuals) practical around reliably tracking absence signs. first study open label dose finding early manifest disease, looking tolerability feasibility exploratory end points ideally engagement. In conclusion, exploring clear rationale base, now take trials. collaborative authors funded European Union's Horizon 2020 Research Innovation Programme under grant agreement No 874758 – Consortium Nsc-Reconstruct: Novel Strategies Cell based Neural Reconstruction (2020-23).

Язык: Английский

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Hybrid nanostructures for neurodegenerative disease theranostics: the art in the combination of biomembrane and non-biomembrane nanostructures

Translational Neurodegeneration, Год журнала: 2024, Номер 13(1)

Опубликована: Авг. 27, 2024

Abstract The diagnosis of neurodegenerative diseases (NDDs) remains challenging, and existing therapeutic approaches demonstrate little efficacy. NDD drug delivery can be achieved through the utilization nanostructures, hence enabling multimodal theranostics. Nevertheless, both biomembrane non-biomembrane nanostructures possess intrinsic shortcomings that must addressed by hybridization to create novel with versatile applications in Hybrid display improved biocompatibility, inherent targeting capabilities, intelligent responsiveness, controlled release. This paper provides a concise overview latest developments hybrid for theranostics emphasizes various engineering methodologies integration diverse including liposomes, exosomes, cell membranes, such as polymers, metals, hydrogels. use combination technique significantly augment precision, intelligence, efficacy therefore functioning more robust theranostic approach NDDs. also addresses issues arise translation explores potential future prospects this field.

Язык: Английский

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Influence of APOE4 genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer's disease continuum

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 102(1), С. 162 - 172

Опубликована: Окт. 15, 2024

Alterations in factors involved cholesterol homeostasis are critical Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with

Язык: Английский

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In Silico Tools to Score and Predict Cholesterol–Protein Interactions

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Cholesterol is structurally distinct from other lipids, which confers it with singular roles in membrane organization and protein function. As a signaling molecule, cholesterol engages discrete interactions transmembrane, peripheral, certain soluble proteins to control cellular responses. Accordingly, the cholesterol-protein interface central cholesterol-related diseases an essential consideration drug design. However, cholesterol's hydrophobic, un-drug-like nature presents unique challenge traditional

Язык: Английский

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Statin use is associated with higher white matter hyperintensity volumes and lower grey matter volumes

Brain Communications, Год журнала: 2024, Номер 6(6)

Опубликована: Янв. 1, 2024

Abstract While statins are routinely prescribed to prevent cardiovascular diseases, their effects on brain alterations remain largely unknown. Very few studies have examined the differences in volumes between statin users and non-users, existing research has yielded inconsistent results. This cross-sectional study aims investigate association use at baseline global specific measured 9 years later a large population-based sample of middle-aged older adults. Participants from UK Biobank without neurological psychiatric disorders consisted 3285 (mean 60 69% males) 36 229 non-users 55 46% males). We used linear models estimate mean volumetric while adjusting for assessment centre, age, sex, ethnicity, education, apolipoprotein E ɛ4 status, Townsend deprivation index, antidepressant use, intracranial volume, lifestyle factors (alcohol intake frequency, smoking physical activity) health-related conditions (body mass blood pressure, diabetes, coronary heart disease, stroke, head injury, depression insomnia). Moreover, mediation analysis was performed evaluate whether mediated by total serum cholesterol concentration. Statin associated with lower grey matter volume [β = −1575 mm3 (−2358, −791)], 20% this also peripheral cortical −1448 (−2227, −668)] higher white hyperintensity 0.11 (0.07, 0.15)]. However, did not differ significantly non-users. Further analyses revealed that thalamus, pallidum, hippocampus, nucleus accumbens other regions temporal lobe were smaller among compared showed is later, indicative brain’s ageing process. observed partially explained statin-induced reduction. emphasizes potential direct indirect volume.

Язык: Английский

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Steroidogenic Acute Regulatory Protein Mediated Variations of Gender-Specific Sex Neurosteroids in Alzheimer’s Disease: Relevance to Hormonal Imbalance

Neuroscience & Biobehavioral Reviews, Год журнала: 2024, Номер 169, С. 105969 - 105969

Опубликована: Дек. 3, 2024

Язык: Английский

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Zebrafish navigating the metabolic maze: insights into human disease – assets, challenges and future implications

Journal of Diabetes & Metabolic Disorders, Год журнала: 2024, Номер 24(1)

Опубликована: Дек. 16, 2024

Язык: Английский

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A cutting-edge approach based on UHPLC-MS to simultaneously investigate oxysterols and cholesterol precursors in biological samples: Validation in Huntington's disease mouse model

Talanta Open, Год журнала: 2023, Номер 9, С. 100278 - 100278

Опубликована: Дек. 6, 2023

Brain is most cholesterol-rich organ in the body. Since cholesterol does not cross blood brain barrier, its metabolism provided situ by astrocytes and neurons, it crucial for maintaining sterol levels neuronal integrity function. Recent studies have shown that of precursors metabolites are lower brains animal models Huntington's disease (HD) while reduced catabolite detected plasma patients. In this study, we introduce a novel analytical method designed to fulfil complex requirements associated with detection neurodegenerative disorders. The allows simultaneous quantification specific set oxysterols along biological samples. proposed uses an Ultra-High-Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS) system operating multiple reaction monitoring (MRM). sterols can be found matrices either free form or esterified various fatty acids, three-step extraction procedure was devised, consisting alkaline hydrolysis, liquid-liquid final concentration omitting need solid-phase (SPE) step. validated achieved limit 10 ng/mL 1 ng/mg tissue, reaching comparable sensitivity previously published LC-MS GC-MS methods. All target analytes were separated on reverse-phase column employing segmented gradient temperature ramp. This strategy enabled elution separation all selected within 30-minutes timeframe. innovative approach employed quantify both samples from wild-type (WT) R6/2 mice, mouse model HD. results obtained sample analysis highlighted significant reduction desmosterol at 12 weeks. conclusion, paves way further development high-sensitive reproducible protocols comprehensively investigate alterations biosynthesis catabolism HD

Язык: Английский

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