Role of GBA variants in Lewy body disease neuropathology

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Март 12, 2024

Язык: Английский

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Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease

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

Опубликована: Сен. 12, 2024

Язык: Английский

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Challenges in Gaucher disease: Perspectives from an expert panel

Molecular Genetics and Metabolism, Год журнала: 2025, Номер unknown, С. 109074 - 109074

Опубликована: Март 1, 2025

Язык: Английский

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The Consequences of GBA Deficiency in the Autophagy–Lysosome System in Parkinson’s Disease Associated with GBA

Cells, Год журнала: 2023, Номер 12(1), С. 191 - 191

Опубликована: Янв. 3, 2023

GBA gene variants were the first genetic risk factor for Parkinson’s disease. encodes lysosomal enzyme glucocerebrosidase (GBA), which is involved in sphingolipid metabolism. exhibits a complex physiological function that includes not only degradation of its substrate glucosylceramide but also metabolism other sphingolipids and additional lipids such as cholesterol, particularly when activity deficient. In context disease associated with GBA, loss has been accumulation α-synuclein species. recent years, several hypotheses have proposed alternative complementary pathological mechanisms to explain why mutations lead become important factors etiology. Classically, linked dysfunctional autophagy–lysosome system subsequent decrease autophagy-dependent turnover; however, underlying GBA-associated parkinsonism proposed. This review summarizes discusses different special focus on mechanisms, well autophagy-independent where role players sphingolipids, cholesterol GBA-related proteins make contributions pathogenesis.

Язык: Английский

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The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson’s Disease: a New Genetic State of the Art

Molecular Neurobiology, Год журнала: 2024, Номер 61(9), С. 6754 - 6770

Опубликована: Фев. 13, 2024

Язык: Английский

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Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease

npj Parkinson s Disease, Год журнала: 2023, Номер 9(1)

Опубликована: Май 11, 2023

Abstract Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in form pathology. While most cases sporadic, there rare genetic mutations that cause more common variants increase incidence disease. The prominent for PD DLB GBA1 LRRK2 genes. associated decreased glucocerebrosidase activity lysosomal its lipid substrates, glucosylceramide glucosylsphingosine. Previous studies have shown a link between this enzyme lipids even sporadic PD. However, it is unclear how protein pathologies related to glycosphingolipid levels. To address gap knowledge, we examined quantitative pathology, substrates parallel from 4 regions 91 brains no neurological disease, idiopathic, -linked, or -linked DLB. We find several biomarkers altered respect mutation progression dementia. found mild association but strong glucosylsphingosine irrespective mutation. This suggests pathology precipitates changes levels

Язык: Английский

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Genetics of Parkinson’s Disease: state-of-the-art and role in clinical settings

Neurologia i Neurochirurgia Polska, Год журнала: 2024, Номер 58(1), С. 38 - 46

Опубликована: Янв. 4, 2024

Язык: Английский

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The lysosomal β-glucocerebrosidase strikes mitochondria: implications for Parkinson’s therapeutics

Brain, Год журнала: 2024, Номер 147(8), С. 2610 - 2620

Опубликована: Март 1, 2024

Abstract Parkinson’s disease is a neurodegenerative disorder primarily known for typical motor features that arise due to the loss of dopaminergic neurons in substantia nigra. However, precise molecular aetiology still unclear. Several cellular pathways have been linked disease, including autophagy-lysosome pathway, α-synuclein aggregation and mitochondrial function. Interestingly, mechanistic link between GBA1, gene encodes lysosomal β-glucocerebrosidase (GCase), lies interplay GCase functions lysosome mitochondria. mutations alter mitochondria-lysosome contact sites. In lysosome, reduced activity leads glycosphingolipid build-up, disrupting function autophagy, thereby triggering accumulation. Additionally, aggregates reduce activity, creating self-perpetuating cycle dysfunction can also be imported into mitochondria, where it promotes integrity complex I. Thus, impair its normal increase oxidative stress compartment dopamine oxidized. turn, accumulation oxidized adducts further impairs second dysfunction. The state triggered by induce DNA damage which, cause cell death. this review, we highlight pivotal role pathogenesis discuss promising examples GCase-based therapeutics, such as enzyme replacement therapies, small molecule chaperones substrate reduction among others, potential therapeutic interventions.

Язык: Английский

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Neuronopathic GBA1L444P Mutation Accelerates Glucosylsphingosine Levels and Formation of Hippocampal Alpha-Synuclein Inclusions

Journal of Neuroscience, Год журнала: 2022, Номер 43(3), С. 501 - 521

Опубликована: Дек. 7, 2022

The most common genetic risk factor for Parkinson's disease (PD) is heterozygous mutations GBA1 , which encodes the lysosomal enzyme, glucocerebrosidase. Reduced glucocerebrosidase activity associates with an accumulation of abnormal α-synuclein (α-syn) called Lewy pathology, characterizes PD. PD patients neuronotypic GBA1L444P mutation (GBA1 +/L444P ) have a 5.6-fold increased cognitive impairments. In this study, we used mice either sex to determine its effects on lipid metabolism, expression synaptic proteins, behavior, and α-syn inclusion formation. At 3 months age, demonstrated impaired contextual fear conditioning, motor activity. Hippocampal levels vGLUT1 were selectively reduced in mice. We show, using mass spectrometry, that glucosylsphingosine, but not glucosylceramide, brains serum Templated induction pathology showed increase formation hippocampus compared +/+ mice, cortex, or substantia nigra pars compacta. Pathologic SNc dopamine neurons by 50% both Treatment GlcCer synthase inhibitor did affect abundance inclusions rescue neuron loss. Overall, these data suggest importance evaluating contribution elevated glucosylsphingosine phenotypes. Further, our may cause defects hippocampus, be mechanism decline more prevalent individuals GBA1-PD. SIGNIFICANCE STATEMENT dementia bodies ( DLB are pathologically characterized (α-syn). Mutant DLB. Our show impairs behaviors related hippocampal function, reduces excitatory protein, susceptible strengthen support These outcomes potential mechanisms contributes symptoms clinically observed findings also highlight as relevant biomarker future therapeutics.

Язык: Английский

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Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6338 - 6338

Опубликована: Март 28, 2023

Parkinson's disease (PD) is the second most common neurodegenerative disorder in aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD related many dysfunctional cellular mechanisms, however, its monogenic forms are caused by pathogenic variants genes involved endolysosomal function (LRRK2, VPS35, VPS13C, ATP13A2) synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, DNAJC6). Moreover, an extensive search for risk revealed strong several lysosomal (e.g., GBA1, SMPD1, TMEM175, SCARB2) highlighting key role dysfunction pathogenesis. Furthermore, large genetic studies that status associated with overall "lysosomal burden", namely cumulative effect weak affecting genes. In this context, understanding complex mechanisms impaired vesicular endolysosomes dopaminergic neurons patients a fundamental step identifying precise therapeutic targets developing effective drugs modify process PD.

Язык: Английский

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