Glucocerebrosidase: Functions in and Beyond the Lysosome

Boer, Daphne E.C.; Smeden, Jeroen van; Bouwstra, Joke A.; Aerts, Johannes M. F. G.

doi:10.3390/jcm9030736

Cited by 47 publications

(39 citation statements)

References 284 publications

(343 reference statements)

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“…196 GlcSph is a biologically active lipid with apparent toxic features. 165 Indeed, excessive GlcSph 197 and GlcCer 61 levels promote α-Syn aggregation in PD models. Notably, although reduced GCase activity is found in different brain regions of patients with PD (as mentioned earlier), there is not much evidence of GCase substrate accumulation in PD brain.…”

Section: Gba1-pd Multilamellar Bodies In Lb Formationmentioning

confidence: 99%

“…200 In the skin, keratinocytes produce specific lamellar bodies that contain large amounts of GlcCer molecules, transported by ABCA12 (ATP-binding cassette subfamily A, member 12), with unique Cer moieties, along with GCase. 165 The lamellar bodies are extruded to the outermost layer of skin, the stratum corneum, where GCase converts the GlcCer to Cer molecules, a modification that is essential for the generation of lipid lamellae with appropriate skin barrier features. 165 Defects in ABCA12 and GCase cause marked skin barrier abnormalities; in severe cases, these are incompatible with terrestrial life.…”

Section: Lamellar Bodies In Skin and Lungmentioning

confidence: 99%

“…A careful analysis of GlcChol levels in PD‐ GBA1 brain seems warranted. The various aspects of GlcChol generation have recently been reviewed 163‐165 …”

Section: Cholesterol In Pdmentioning

confidence: 99%

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

2020

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

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Section: Gba1-pd Multilamellar Bodies In Lb Formationmentioning

confidence: 99%

Section: Lamellar Bodies In Skin and Lungmentioning

confidence: 99%

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

2020

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“…First described nearly 140 years ago, Gaucher disease arises through autosomal recessive inheritance of a GBA1 gene mutation, leading to a deficiency in the activity of lysosomal glucocerebrosidase (also known as glucosylceramidase or acid β‐glucosidase) 1,2 . Deficiency of this enzyme results in accumulation of glycosphingolipid substrates such as glucocerebroside, primarily within the lysosomal compartment of macrophages 2–5 . Engorged, lipid‐laden macrophage cells (‘Gaucher cells’) infiltrate the bone marrow and visceral organs, displacing normal cells 3 and resulting in multi‐system disease 2 …”

Section: Gaucher Disease: a Multi‐organ Disorder With A Heterogeneousmentioning

confidence: 99%

Treatable lysosomal storage diseases in the advent of disease‐specific therapy

Peters

Ellaway

Nicholls

et al. 2020

Internal Medicine Journal

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Lysosomal storage diseases (LSD) comprise a rare and heterogeneous group of nearly 50 heritable metabolic disorders caused by mutations in proteins critical for cellular lysosomal function. Defects in the activity of these proteins in multiple organs leads to progressive intra‐lysosomal accumulation of specific substrates, resulting in disruption of cellular functions, extracellular inflammatory responses, tissue damage and organ dysfunction. The classification and clinical presentation of different LSD are dependent on the type of accumulated substrate. Some clinical signs and symptoms are common across multiple LSD, while others are more specific to a particular syndrome. Due to the rarity and wide clinical diversity of LSD, identification and diagnosis can be challenging, and in many cases diagnosis is delayed for months or years. Treatments, such as enzyme replacement therapy, haemopoietic stem cell transplantation and substrate reduction therapy, are now available for some of the LSD. For maximum effect, therapy must be initiated prior to the occurrence of irreversible tissue damage, highlighting the importance of prompt diagnosis. Herein, we discuss the clinical presentation, diagnosis and treatment of four of the treatable LSD: Gaucher disease, Fabry disease, Pompe disease, and two of the mucopolysaccharidoses (I and II). For each disease, we present illustrative case studies to help increase awareness of their clinical presentation and possible treatment outcomes.

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“…Glucocerebrosidase (GCase) is a 497 amino-acid lysosomal hydroxylase, which degrades glucocerebroside into ceramide and glucose (Boer et al 2020 ). Individuals that are homogenous for pathogenic variants of GBA, the gene encoding GCase, develop Gaucher’s disease due to excessive storage of glucocerebroside in the liver, spleen, bone, and bone marrow (Beutler 2001 ).…”

Section: Introductionmentioning

confidence: 99%

Novel targeted therapies for Parkinson’s disease

Ntetsika

Papathoma

Markaki

2021

Mol Med

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Parkinson’s disease (PD) is the second more common neurodegenerative disease with increasing incidence worldwide associated to the population ageing. Despite increasing awareness and significant research advancements, treatment options comprise dopamine repleting, symptomatic therapies that have significantly increased quality of life and life expectancy, but no therapies that halt or reverse disease progression, which remain a great, unmet goal in PD research. Large biomarker development programs are undertaken to identify disease signatures that will improve patient selection and outcome measures in clinical trials. In this review, we summarize PD-related mechanisms that can serve as targets of therapeutic interventions aiming to slow or modify disease progression, as well as previous and ongoing clinical trials in each field, and discuss future perspectives.

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Glucocerebrosidase: Functions in and Beyond the Lysosome

Cited by 47 publications

References 284 publications

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

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

Treatable lysosomal storage diseases in the advent of disease‐specific therapy

Novel targeted therapies for Parkinson’s disease

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