Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects

Neurobiology of Disease, Год журнала: 2024, Номер 196, С. 106505 - 106505

Опубликована: Апрель 19, 2024

Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features AD memory decline cognitive dysfunction, while PD mainly manifests as motor dysfunction such limb tremors, muscle rigidity abnormalities, slow gait. Abnormalities in cholesterol, sphingolipid, glycerophospholipid metabolism have been demonstrated to directly exacerbate progression by stimulating Aβ deposition tau protein tangles. Indirectly, abnormal lipids can increase burden on brain vasculature, induce insulin resistance, affect structure neuronal cell membranes. Abnormal lipid leads through inducing accumulation α-syn, mitochondria endoplasmic reticulum, ferroptosis. Great progress has made targeting abnormalities for treatment recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, monoclonal antibodies apolipoprotein E (ApoE). This review comprehensively summarizes involvement dysregulated pathogenesis PD, application Lipid Monitoring, emerging regulatory drug targets. A better understanding lipidological bases may pave way developing effective prevention methods neurodegenerative disorders.

Язык: Английский

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Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

Movement Disorders, Год журнала: 2018, Номер 33(5), С. 684 - 696

Опубликована: Апрель 27, 2018

The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. discovery genetic variants causing and/or increasing risk for PD has provided field with a new arsenal potential therapies ready to be tested clinical trials. We highlight 3 discoveries (α-synuclein, glucocerebrosidase, and leucine-rich repeat kinase) have prompted therapeutic approaches now entering stages. are at an exciting juncture journey developing disease-modifying based on knowledge genetics pathology. This review focuses paradigms under development highlights wide range key outstanding questions PD. © 2018 Authors. Movement Disorders published by Wiley Periodicals, Inc. behalf International Parkinson Disorder Society.

Язык: Английский

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Is Parkinson’s disease a lysosomal disorder?

Brain, Год журнала: 2018, Номер 141(8), С. 2255 - 2262

Опубликована: Май 9, 2018

Common forms of Parkinson's disease have long been described as idiopathic, with no single penetrant genetic factor capable influencing aetiology. Recent studies indicate a clear association variants within several lysosomal genes risk factors for idiopathic disease. The emergence novel suggest that the aetiology may be explained by interaction partially mutations that, while seemingly complex, all appear to converge on cellular clearance pathways. These newly evolving data are consistent mechanistic linking α-synuclein toxicity abnormalities, and resembles features Mendelian storage disorders at biochemical level. findings offer pathways exploit development disease-altering therapies target specific components system.

Язык: Английский

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APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid

Science Translational Medicine, Год журнала: 2020, Номер 12(529)

Опубликована: Фев. 5, 2020

The apolipoprotein E (

Язык: Английский

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Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

Frontiers in Molecular Neuroscience, Год журнала: 2017, Номер 10

Опубликована: Ноя. 16, 2017

Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity diverse signaling platforms pathways. Particularly enriched in brain, cholesterol homeostasis this organ singular with respect to other tissues exhibits heterogeneous regulation distinct brain cell populations. Due role physiology function, alterations levels have been linked diseases neurodegeneration. In case Alzheimer's disease (AD), however, association remains unclear evidence indicating that either increased or decreased total contribute major neurodegenerative disease. Here, rather than analyzing neurodegeneration, we focus on intracellular pools, particularly endolysosomes mitochondria through its trafficking via specialized domains delineated contacts between endoplasmic reticulum mitochondria, onset prevalent such as AD, Parkinson Huntington well lysosomal disorders like Niemann Pick type C We dissect molecular events associated accumulation, especially an event results impaired mitochondrial antioxidant defense function. A better understanding mechanisms involved distribution compartments may shed light disruption neurodegeneration pave way for specific intervention opportunities.

Язык: Английский

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Prion-Like Mechanisms in Parkinson’s Disease

Frontiers in Neuroscience, Год журнала: 2019, Номер 13

Опубликована: Июнь 18, 2019

Formation and aggregation of misfolded proteins in the central nervous system (CNS) is a key hallmark several age-related neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's (AD), amyotrophic lateral sclerosis (ALS). These diseases share biophysical biochemical characteristics with prion diseases. It believed that PD characterized by abnormal protein aggregation, mainly α-synuclein (α-syn). Of particular importance, there growing evidence indicating α-syn can spread to neighboring brain regions cause endogenous these as seeds, "prion-like" manner. Abundant studies vitro vivo have shown goes through templated conformational change, propagates from original region regions, eventually neuron degeneration substantia nigra striatum. The objective this review summarize mechanisms involved intracellular its subsequent cell-to-cell transmission. According findings, we look forward effective therapeutic perspectives block progression

Язык: Английский

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Exploring Sphingolipid Implications in Neurodegeneration

Frontiers in Neurology, Год журнала: 2020, Номер 11

Опубликована: Май 21, 2020

Over the past decade, it was found that relatively simple sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate and glucosylceramide play important roles in neuronal functions by regulating rates of growth differentiation. Homeostasis membrane sphingolipids neurons myelin is essential to prevent loss synaptic plasticity, cell death neurodegeneration. In our review we summarize data about significant brain alterations different neurodegenerative diseases Alzheimer's disease, Parkinson Amyotrophic Lateral Sclerosis, Gaucher's, Farber's diseases, etc. We reported results obtained tissue from both animals which were induced humans autopsy samples. Moreover, attention paid on biofluids, liquor blood, patients. disease are involved processing aggregation β-amyloid transmission cytotoxic signal TNFinduced. Recently, gangliosides metabolism transgenic relationship between blood changes cognitive impairment patients have been intensively studied. Numerous experiments highlighted involvement ceramide monohexosylceramide pathophysiology sporadic forms Parkinson's disease. gene mutations glucocerebrosidase enzyme considered responsible for via transition monomeric form α-synuclein an oligomeric, aggregated toxic form. Disturbances ceramides also associated with appearance Lewy's bodies. Changes sphingolipid a manifestation family forms, affected rate development. Currently, fingolimod (FTY720), receptor modulator, only drug undergoing clinical trials phase II safety treatment Sclerosis. The use new diagnostic markers targets innovative therapeutic strategies disorders has included.

Язык: Английский

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In situ architecture of neuronal α-Synuclein inclusions

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Апрель 14, 2021

Abstract The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly fibrils, but recent reports pointed intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) image neuronal in situ at resolution. We show that seeded by aggregates produced recombinantly or purified from patient brain fibrils crisscrossing a variety cellular organelles. Using gold-labeled seeds, find aggregate seeding is predominantly mediated small which cytoplasmic grow unidirectionally. Detailed analysis membrane interactions revealed do not contact directly, and does drive clustering. Altogether, conclusively demonstrate intermixed with membranous organelles, illuminate mechanism interaction.

Язык: Английский

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Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Movement Disorders, Год журнала: 2018, Номер 34(1), С. 9 - 21

Опубликована: Дек. 27, 2018

Abstract Glucocerebrosidase is a lysosomal enzyme. The characterization of direct link between mutations in the gene coding for glucocerebrosidase ( GBA1 ) with development Parkinson's disease and dementia Lewy bodies has heightened interest this Although mechanisms through which regulates homeostasis α‐synuclein remains poorly understood, identification reduced activity brains patients PD paved way novel therapeutic strategies directed at enhancing reducing burden, thereby slowing down or even preventing neuronal death. Here we reviewed current literature relating to underlying cross talk α‐synuclein, mutation‐associated clinical phenotypes, ongoing approaches targeting glucocerebrosidase. © 2018 International Parkinson Movement Disorder Society

Язык: Английский

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

Movement Disorders, Год журнала: 2020, Номер 36(5), С. 1070 - 1085

Опубликована: Ноя. 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

Язык: Английский

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