Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues

Pharmacology & Therapeutics, Год журнала: 2023, Номер 246, С. 108419 - 108419

Опубликована: Апрель 19, 2023

The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants cause Gaucher disease (GD), a storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation substrates. Carriers have an increased risk developing Parkinson (PD), with odds ratio ranging from 2.2 to 30 according variant severity. do not GD homozygosis can also increase PD risk. Patients carrying show more rapidly progressive phenotype compared non-carriers, emphasising need for modifying treatments targeting pathway. Several mechanisms secondary dysfunction are potentially responsible pathological changes leading PD. Misfolded proteins induce endoplasmic reticulum stress subsequent unfolded protein response impair autophagy-lysosomal This results α-synuclein spread, promotes neurodegenerative changes. Preclinical evidence shows that products promote α-synuclein, however there no convincing substrate GBA1-PD brains. Altered lipid homeostasis could contribute pathology. Treatments target pathway reverse these processes halt/slow progression These range augmentation via therapy, restoration normal trafficking molecular chaperones, reduction therapy. review discusses pathways associated related novel GBA1-targeted interventions treatment.

Язык: Английский

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Gaucher disease provides a unique window into Parkinson disease pathogenesis

Nature Reviews Neurology, Год журнала: 2024, Номер 20(9), С. 526 - 540

Опубликована: Авг. 6, 2024

Язык: Английский

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GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Март 7, 2024

Abstract Background Mutations in the β-glucocerebrosidase ( GBA1 ) gene do cause lysosomal storage Gaucher disease (GD) and are among most frequent genetic risk factors for Parkinson’s (PD). So far, studies on both neuronopathic GD PD primarily focused neuronal manifestations, besides evaluation of microglial astrocyte implication. White matter alterations were described central nervous system paediatric type 1 patients suggested to sustain or even play a role process, although contribution oligodendrocytes has been so far scarcely investigated. Methods We exploited study induction myelination vitro, consisting Oli-neu cells treated with dibutyryl-cAMP, order evaluate expression levels function during oligodendrocyte differentiation. Conduritol-B-epoxide, irreversible inhibitor was used dissect impact inactivation process myelination, degradation α-synuclein accumulation vitro. Moreover, white vivo, we developed novel mouse transgenic line which is abolished myelinating glia, by crossing Cnp1-cre bearing loxP sequences flanking Gba1 exons 9–11, encoding catalytic domain. Immunofluorescence, western blot lipidomic analyses performed brain samples from wild-type knockout animals assess onset early neurodegenerative hallmarks, together differentiation analysis primary cultures. Results Here show that induces dysfunction inhibits oligodendrocyte-specific loss-of-function sufficient induce vivo demyelination including axonal degeneration, astrogliosis, lipid dyshomeostasis functional impairment. Conclusions Our sheds light GBA1-related diseases supports need better characterizing as actors playing diseases, also pointing at them potential targets set brake progression.

Язык: Английский

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Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives

Physiological Reviews, Год журнала: 2024, Номер 105(1), С. 137 - 207

Опубликована: Июль 11, 2024

Lipids represent the most abundant molecular type in brain, with a fat content of ∼60% dry brain weight humans. Despite this fact, little attention has been paid to circumscribe dynamic role lipids function and disease. Membrane such as cholesterol, phosphoinositide, sphingolipids, arachidonic acid, endocannabinoids finely regulate both synaptic receptors ion channels that ensure critical neural functions. After brief introduction on their respective properties, we review here regulating channel activity, action potential propagation, neuronal development, functional plasticity contribution development neurological neuropsychiatric diseases. We also provide possible directions for future research lipid

Язык: Английский

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Mechanisms of Glucocerebrosidase Dysfunction in Parkinson’s Disease

Journal of Molecular Biology, Год журнала: 2023, Номер 435(12), С. 168023 - 168023

Опубликована: Фев. 23, 2023

Beta-glucocerebrosidase is a lysosomal hydrolase, encoded by GBA1 that represents the most common risk gene associated with Parkinson's disease (PD) and Lewy Body Dementia. Glucocerebrosidase dysfunction has been also observed in absence of mutations across different genetic sporadic forms PD related disorders, suggesting broader role glucocerebrosidase neurodegeneration. In this review, we highlight recent advances mechanistic characterization function as foundation for development novel therapeutics targeting disorders.

Язык: Английский

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Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease

Frontiers in Neurology, Год журнала: 2022, Номер 13

Опубликована: Авг. 12, 2022

Variants in the GBA1 and LRRK2 genes are most common genetic risk factors associated with Parkinson disease (PD). Both lysosomal autophagic pathways, gene encoding for enzyme, glucocerebrosidase (GCase) leucine-rich repeat kinase 2 enzyme. -associated PD is characterized by earlier age at onset more severe non-motor symptoms compared to sporadic PD. Mutations can be stratified into severe, mild variants depending on clinical presentation of disease. a loss- gain- function hypothesis has been proposed functional consequences each variant often linked mutation severity. On other hand, similar PD, but benign course. occur several structural domains affect phosphorylation GTPases. Biochemical studies suggest possible convergence double mutant carriers showing milder phenotype This review compares highlights genotype-phenotype associations separately, based biochemical single variants.

Язык: Английский

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Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Сен. 3, 2024

In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons terminally differentiated post-mitotic cells. Neuronal function elimination depend on normal lysosomal function. Converging data suggest dysfunction is critical event the etiology of Parkinson's disease (PD). Mutations Glucosylceramidase Beta 1 (GBA1) leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for development parkinsonism. Furthermore, has been observed affected neurons sporadic PD (sPD) patients. Given hydrolases actively contribute to breakdown impaired organelles misfolded proteins, any compromise integrity could incite abnormal accumulation including α-synuclein, major component Lewy bodies PD. Clinical observations have shown levels cerebrospinal fluid may serve as potential biomarkers diagnosis signs dysfunction. this review, we summarize current evidence regarding discuss intimate relationship between pathological α-synuclein. addition, therapeutic strategies target treat

Язык: Английский

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Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson’s Disease

Cellular and Molecular Neurobiology, Год журнала: 2025, Номер 45(1)

Опубликована: Март 26, 2025

Worldwide aging has contributed to the growth of prevalence neurodegenerative diseases (NDDs), including Parkinson's disease among elderlies. The advanced destruction dopaminergic neurons in substantia nigra, due many accelerator factors brain is main mechanism disease. pathological aggregated alpha-synuclein (α-syn), a protein implicated multiple disorders, one critical this and other similar disorders. misfolding aggregation α-syn may interrupt processes, functions synaptic vesicles can lead neuronal death. This encoded by Alpha-Synuclein Gene (SNCA) mutation gene dysfunctions structure. Since, therapeutic policies that aim are promising approaches. Advances immunotherapies, molecular chaperones, therapy targeting SNCA, DNA aptamers some examples strategy. review aims comprehensively assess current knowledge evidence on pathology, genetic determinants, novel methods Parkinson,'s synucleinopathies. Continued investigation discover interventions system could result finding effective safe treatments for NDDs.

Язык: Английский

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Astrocytes in Parkinson’s Disease: From Role to Possible Intervention

Cells, Год журнала: 2023, Номер 12(19), С. 2336 - 2336

Опубликована: Сен. 22, 2023

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons. While neuronal dysfunction central to PD, astrocytes also play important roles, both positive and negative, such roles have not yet been fully explored. This literature review serves highlight these how properties can be used increase neuron survivability. Astrocytes normally protective functions, as releasing neurotrophic factors, metabolizing glutamate, transferring healthy mitochondria neurons, or maintaining blood–brain barrier. However, in become dysfunctional contribute neurotoxicity, e.g., via impaired glutamate metabolism release inflammatory cytokines. Therefore, represent double-edged sword. Restoring astrocyte function increasing beneficial effects represents promising therapeutic approach. Strategies promoting neurotrophin release, preventing harmful reactivity, utilizing regional diversity may help restore neuroprotection.

Язык: Английский

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A Comparative Biochemical and Pathological Evaluation of Brain Samples from Knock-In Murine Models of Gaucher Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(3), С. 1827 - 1827

Опубликована: Фев. 2, 2024

Gaucher disease (GD) is a lysosomal storage disorder stemming from biallelic mutations in GBA1, characterized by glucocerebrosidase dysfunction and glucocerebroside glucosylsphingosine accumulation. Since phenotypes of murine models GD often differ those patients, the careful characterization Gba1 mutant mice necessary to establish their ability model GD. We performed side-by-side comparative biochemical pathologic analyses four with genotypes L444P/L444P (p.L483P/p.L483P), L444P/null, D409H/D409H (p.D448H/p.D448H) D409H/null, along matched wildtype mice, all same genetic background cage conditions. All exhibited significantly lower activity (p < 0.0001) higher levels than wildtype, lowest highest carrying null allele. Although L444P D409H was similar, showed more lipid No or storage-like cells were detected any mice. Quantification neuroinflammation, dopaminergic neuronal loss, alpha-synuclein motor behavior revealed no significant findings, even aged animals. Thus, while may have utility for testing effect different therapies on enzymatic activity, they did not recapitulate pathological phenotype patients GD, better are needed.

Язык: Английский

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