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Journal articles on the topic 'GBA1 gene'

Author: Grafiati

Published: 3 June 2025

Last updated: 31 July 2025

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1

Cabasso, Or, Sumit Paul, Gali Maor, et al. "The Uncovered Function of the Drosophila GBA1a-Encoded Protein." Cells 10, no. 3 (2021): 630. http://dx.doi.org/10.3390/cells10030630.

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Human GBA1 encodes lysosomal acid β-glucocerebrosidase (GCase), which hydrolyzes cleavage of the beta-glucosidic linkage of glucosylceramide (GlcCer). Mutations in this gene lead to reduced GCase activity, accumulation of glucosylceramide and glucosylsphingosine, and development of Gaucher disease (GD). Drosophila melanogaster has two GBA1 orthologs. Thus far, GBA1b was documented as a bone fide GCase-encoding gene, while the role of GBA1a encoded protein remained unclear. In the present study, we characterized a mutant variant of the fly GBA1a, which underwent ERAD and mildly activated the UP

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Kuppuramalingam, Aparna, Or Cabasso, and Mia Horowitz. "Functional Analysis of Human GBA1 Missense Mutations in Drosophila: Insights into Gaucher Disease Pathogenesis and Phenotypic Consequences." Cells 13, no. 19 (2024): 1619. http://dx.doi.org/10.3390/cells13191619.

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The human GBA1 gene encodes lysosomal acid β-glucocerebrosidase, whose activity is deficient in Gaucher disease (GD). In Drosophila, there are two GBA1 orthologs, Gba1a and Gba1b, and Gba1b is the bona fide GCase encoding gene. Several fly lines with different deletions in the Gba1b were studied in the past. However, since most GD-associated GBA1 mutations are point mutations, we created missense mutations homologous to the two most common GD mutations: the mild N370S mutation (D415S in Drosophila) and the severe L444P mutation (L494P in Drosophila), using the CRISPR-Cas9 technology. Flies hom

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Atilano, Magda L., Alexander Hull, Catalina-Andreea Romila, et al. "Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease." PLOS Genetics 19, no. 12 (2023): e1011063. http://dx.doi.org/10.1371/journal.pgen.1011063.

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Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest known genetic risk factors for Parkinson’s disease (PD). Communication between the gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1, display widespread NF-kB signalling activation, including gut inflammation, and brain glial activation. We also demonstrate intestinal autophagic defects, gut dysfunction, and microbiome dysbiosis. Remarkably, mod

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Cabasso, Paul, Dorot, et al. "Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease." Journal of Clinical Medicine 8, no. 9 (2019): 1420. http://dx.doi.org/10.3390/jcm8091420.

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Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, type 2 and type 3, forms. We studied the two fly GBA1 orthologs, GBA1a and GBA1b. Each contains a Minos element insertion, which truncates its coding sequence. In the GBA1am/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. How

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Skrahin, Aliaksandr, Mia Horowitz, Majdolen Istaiti, et al. "GBA1-Associated Parkinson’s Disease Is a Distinct Entity." International Journal of Molecular Sciences 25, no. 13 (2024): 7102. http://dx.doi.org/10.3390/ijms25137102.

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GBA1-associated Parkinson’s disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson’s disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit

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Smith, Adam R., David M. Richards, Katie Lunnon, Anthony H. V. Schapira та Anna Migdalska-Richards. "DNA Methylation of α-Synuclein Intron 1 Is Significantly Decreased in the Frontal Cortex of Parkinson’s Individuals with GBA1 Mutations". International Journal of Molecular Sciences 24, № 3 (2023): 2687. http://dx.doi.org/10.3390/ijms24032687.

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Parkinson’s disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7–10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-

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Kojima, Rika, Wojciech Paslawski, Guochang Lyu, Ernest Arenas, Xiaoqun Zhang, and Per Svenningsson. "Secretome Analyses Identify FKBP4 as a GBA1-Associated Protein in CSF and iPS Cells from Parkinson’s Disease Patients with GBA1 Mutations." International Journal of Molecular Sciences 25, no. 1 (2024): 683. http://dx.doi.org/10.3390/ijms25010683.

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Mutations in the GBA1 gene increase the risk of developing Parkinson’s disease (PD). However, most carriers of GBA1 mutations do not develop PD throughout their lives. The mechanisms of how GBA1 mutations contribute to PD pathogenesis remain unclear. Cerebrospinal fluid (CSF) is used for detecting pathological conditions of diseases, providing insights into the molecular mechanisms underlying neurodegenerative disorders. In this study, we utilized the proximity extension assay to examine the levels of metabolism-linked protein in the CSF from 17 PD patients carrying GBA1 mutations (GBA1-PD) an

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Pavan, Eleonora, Paolo Peruzzo, Silvia Cattarossi, et al. "Deficiency of Glucocerebrosidase Activity beyond Gaucher Disease: PSAP and LIMP-2 Dysfunctions." International Journal of Molecular Sciences 25, no. 12 (2024): 6615. http://dx.doi.org/10.3390/ijms25126615.

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Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the proteolytical cleavage of prosaposin (encoded by PSAP gene), which gives rise to four saposins. GCase is targeted to the lysosomes by LIMP-2, encoded by SCARB2 gene. GCase deficiency causes Gaucher Disease (GD), which is mainly due to biallelic pathogenetic variants in the GCase-encoding gene, GBA1. However, impairment of GCase activity can be rarely caused by SapC or LIMP-2 deficiencies. We report a new case of LIMP-2 deficie

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Okai, Takuro, Sho Sato, Mugdha Deshpande та ін. "AAV delivery of GBA1 suppresses α-synuclein accumulation in Parkinson’s disease models and restores functions in Gaucher’s disease models". PLOS One 20, № 5 (2025): e0321145. https://doi.org/10.1371/journal.pone.0321145.

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Biallelic mutations in the glucosylceramidase beta 1 (GBA1) gene are the underlying genetic cause of Gaucher’s disease (GD), resulting in a deficient lysosomal hydrolase and subsequent accumulation of glycosphingolipids. More recently, GBA1 mutations have been identified as the most prevalent genetic risk factor for Parkinson’s disease (PD), associated with more pronounced symptoms characterized by earlier onset and accelerated cognitive decline. In these GBA-associated PD patients the α-synuclein pathology is more prominent, and recent data suggest a link between α-synucleinopathies and GBA1

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Emelyanov, Anton K., Tatiana S. Usenko, Alena E. Kopytova та ін. "Blood Glucocerebrosidase Activity and α-Synuclein Levels in Patients with GBA1-Associated Parkinson's Disease and Asymptomatic <i>GBA1</i> Mutation Carriers". Annals of Clinical and Experimental Neurology 18, № 3 (2024): 50–57. http://dx.doi.org/10.17816/acen.1106.

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Introduction. Mutations in a GBA1 gene, which encodes a lysosomal enzyme called glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). The pathogenesis of PD results from the death of dopaminergic neurons in the substantia nigra of the brain, which is associated with the aggregation of α-synuclein protein. However, not all GBA1 mutation carriers develop PD during their lifetime. The aim of this study was to evaluate GCase activity and α-synuclein levels in CD45+ blood cells of patients with PD associated with GBA1 mutations (GBА1-PD), asymptomatic car

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Granek, Zuzanna, Julia Barczuk, Natalia Siwecka, Wioletta Rozpędek-Kamińska, Ewa Kucharska та Ireneusz Majsterek. "GBA1 Gene Mutations in α-Synucleinopathies—Molecular Mechanisms Underlying Pathology and Their Clinical Significance". International Journal of Molecular Sciences 24, № 3 (2023): 2044. http://dx.doi.org/10.3390/ijms24032044.

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α-Synucleinopathies comprise a group of neurodegenerative diseases characterized by altered accumulation of a protein called α-synuclein inside neurons and glial cells. This aggregation leads to the formation of intraneuronal inclusions, Lewy bodies, that constitute the hallmark of α-synuclein pathology. The most prevalent α-synucleinopathies are Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). To date, only symptomatic treatment is available for these disorders, hence new approaches to their therapy are needed. It has been observed that GBA1 mutati

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Polinski, Nicole K., Terina N. Martinez, Alexander Gorodinsky, et al. "Decreased glucocerebrosidase activity and substrate accumulation of glycosphingolipids in a novel GBA1 D409V knock-in mouse model." PLOS ONE 16, no. 6 (2021): e0252325. http://dx.doi.org/10.1371/journal.pone.0252325.

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Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher’s disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson’s disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiop

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Stoker, Thomas B., Marta Camacho, Sophie Winder-Rhodes, et al. "Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson’s disease." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 7 (2020): 695–702. http://dx.doi.org/10.1136/jnnp-2020-322857.

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IntroductionVariants in the GBA1 gene have been identified as a common risk factor for Parkinson’s disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of ‘non-pathogenic’ variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of ‘non-pathogenic’ GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up.MethodsThe study population consisted of patients in the C

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Usenko, Tatiana, Anastasia Bezrukova, Margarita M. Rudenok, et al. "Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity." International Journal of Molecular Sciences 24, no. 15 (2023): 12164. http://dx.doi.org/10.3390/ijms241512164.

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Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson’s disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substa

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Brazdis, Razvan-Marius, Claudia von Zimmermann, Bernd Lenz, Johannes Kornhuber та Christiane Mühle. "Peripheral Upregulation of Parkinson’s Disease-Associated Genes Encoding α-Synuclein, β-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression". International Journal of Molecular Sciences 25, № 6 (2024): 3219. http://dx.doi.org/10.3390/ijms25063219.

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Due to the high comorbidity of Parkinson’s disease (PD) with major depressive disorder (MDD) and the involvement of sphingolipids in both conditions, we investigated the peripheral expression levels of three primarily PD-associated genes: α-synuclein (SNCA), lysosomal enzyme β-glucocerebrosidase (GBA1), and UDP-glucose ceramide glucosyltransferase (UGCG) in a sex-balanced MDD cohort. Normalized gene expression was determined by quantitative PCR in patients suffering from MDD (unmedicated n = 63, medicated n = 66) and controls (remitted MDD n = 39, healthy subjects n = 61). We observed that exp

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Pavan, Eleonora, Maximiliano Ormazabal, Paolo Peruzzo, Emilio Vaena, Paula Rozenfeld, and Andrea Dardis. "CRISPR/Cas9 Editing for Gaucher Disease Modelling." International Journal of Molecular Sciences 21, no. 9 (2020): 3268. http://dx.doi.org/10.3390/ijms21093268.

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Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the acid β-glucosidase gene (GBA1). Besides causing GD, GBA1 mutations constitute the main genetic risk factor for developing Parkinson’s disease. The molecular basis of neurological manifestations in GD remain elusive. However, neuroinflammation has been proposed as a key player in this process. We exploited CRISPR/Cas9 technology to edit GBA1 in the human monocytic THP-1 cell line to develop an isogenic GD model of monocytes and in glioblastoma U87 cell lines to generate an isogenic GD model of g

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McGlinchey, Ryan P., та Jennifer C. Lee. "Emerging insights into the mechanistic link between α-synuclein and glucocerebrosidase in Parkinson's disease". Biochemical Society Transactions 41, № 6 (2013): 1509–12. http://dx.doi.org/10.1042/bst20130158.

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Mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase, cause the lysosomal storage disorder GD (Gaucher’s disease), and are associated with the development of PD (Parkinson's disease) and other Lewy body disorders. Interestingly, GBA1 variants are the most common genetic risk factor associated with PD. Although clinical studies argue a strong case towards a link between GBA1 mutations and the development of PD, mechanistic insights have been lacking. In the present article, we review recent findings that have provided some biochemical evidence to bridge this relationship, focusing

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Payne, Thomas, Marcus Keatinge, Marc Da Costa, and Oliver Bandmann. "MPP+ IN A ZEBRAFISH MODEL OF GLUCOCEREBROSIDASE 1 DEFICIENCY." Journal of Neurology, Neurosurgery & Psychiatry 86, no. 11 (2015): e4.93-e4. http://dx.doi.org/10.1136/jnnp-2015-312379.182.

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ObjectiveTo determine if glucocerebrosidase 1 deficiency is a susceptibility factor to 1-methyl-4-phenylpyridinium (MPP+) toxicity using a zebrafish model.Background and hypothesisHeterozygous mutations in the glucocerebrosidase gene (GBA1) are a strong genetic risk factor for Parkinson's disease (PD). Genetic risk factors may increase susceptibility to exogenous neurotoxins. We hypothesized GBA1 haploinsufficiency may increase susceptibility to the classical PD neurotoxin MPTP.MethodsA stable gba1+/− zebrafish line was in-crossed to generate embryos of all genotypes. At 2 days post fertilizat

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Koros, Christos, Anastasia Bougea, Ioanna Alefanti, et al. "A Global Perspective of GBA1-Related Parkinson’s Disease: A Narrative Review." Genes 15, no. 12 (2024): 1605. https://doi.org/10.3390/genes15121605.

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Parkinson’s disease (PD) is considered to be the second most prominent neurodegenerative disease and has a global prevalence. Glucocerebrosidase (GBA1) gene mutations represent a significant hereditary risk factor for the development of PD and have a profound impact on the motor and cognitive progression of the disease. The aim of this review is to summarize the literature data on the prevalence, type, and peculiarities of GBA1 mutations in populations of different ethnic backgrounds. We reviewed articles spanning the 2000–2024 period. GBA1-related PD has a worldwide distribution. It has long

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Sucunza, Diego, Alberto J. Rico, Elvira Roda, et al. "Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques." International Journal of Molecular Sciences 22, no. 9 (2021): 4825. http://dx.doi.org/10.3390/ijms22094825.

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Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson’s disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD—even when considering idiopathic forms of PD—has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease mo

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Ali Ahmed, Ikhlas, and Alaa Abbas Fadhel. "A reappraisal of Gaucher disease patients - Clinical presentation, and diagnosis in rare disease unit of central child teaching hospital in Baghdad province." Biomedicine 43, no. 02 (2023): 735–41. http://dx.doi.org/10.51248/.v43i02.2700.

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Introduction and Aim: Gaucher disease (GD) is an autosomal recessive ailment caused due to mutations in the GBA1 gene, encoding for the lysosomal enzyme, glucocerebrosidase. The aim was to evaluate the clinical, biochemical, and molecular parameters associated with this disease, as well as to identify symptoms and covariables thought to be most diagnostic of early GD presentation, allowing for early diagnosis and management. Methodology: This cross-sectional study involved twenty-six patients diagnosed with GD at the Metabolic Department of Central Child Teaching Hospital, Baghdad, Iraq. Diagn

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Álvarez Jerez, Pilar, Peter Wild Crea, Daniel M. Ramos, et al. "African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1." Nature Structural & Molecular Biology 31, no. 12 (2024): 1955–63. https://doi.org/10.1038/s41594-024-01423-2.

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AbstractRecently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant (rs3115534-G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy

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Anania, Monia, Miriam Giacomarra, Annalisa D’Errico, et al. "Identification of Novel Mutations in Patients Affected by Gaucher Disease." International Journal of Molecular Sciences 26, no. 8 (2025): 3918. https://doi.org/10.3390/ijms26083918.

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Gaucher disease is an autosomal recessive disorder caused by dysfunction of the enzyme glucocerebrosidase. The enzyme deficiency is mainly due to mutations in the GBA1 gene, and it is responsible for the accumulation of glucosylceramide within the lysosomes of monocyte macrophage-derived cells; causing the associated symptomatology. In this paper, we describe six new mutations identified in the GBA1 gene, which, in combination with other mutations already documented, lead to absent or reduced glucocerebrosidase activity, resulting in pathological accumulation of the specific substrate and the

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Et al., Al-Dallee. "Expression of Recombinant Human Glucocerebrosidase Protein in Sunflowers." Baghdad Science Journal 16, no. 1 (2019): 0018. http://dx.doi.org/10.21123/bsj.2019.16.1.0018.

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Molecular farming has become one of the most significant implementations of modern biotechnology to generate modified plant crops to produce medicinal proteins. Agrobacterium is one plant genetic engineering tool that integrates genes of interest inside a host plant. In recent years, the need to produce recombinant proteins as therapeutics has growing rapidly, and human glucocerebrosidase is one of the proteins that is need to treat disease. In this study, specific primers were designed to amplify Hu-GBA1 gene from constructed pGEM-GBA plasmid which was cloned into the plant expression vector

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Et al., Al-Dallee. "Expression of Recombinant Human Glucocerebrosidase Protein in Sunflowers." Baghdad Science Journal 16, no. 1 (2019): 0018. http://dx.doi.org/10.21123/bsj.16.1.0018.

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Molecular farming has become one of the most significant implementations of modern biotechnology to generate modified plant crops to produce medicinal proteins. Agrobacterium is one plant genetic engineering tool that integrates genes of interest inside a host plant. In recent years, the need to produce recombinant proteins as therapeutics has growing rapidly, and human glucocerebrosidase is one of the proteins that is need to treat disease. In this study, specific primers were designed to amplify Hu-GBA1 gene from constructed pGEM-GBA plasmid which was cloned into the plant expression vector

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Burbulla, Lena F., Sohee Jeon, Jianbin Zheng, Pingping Song, Richard B. Silverman, and Dimitri Krainc. "A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease." Science Translational Medicine 11, no. 514 (2019): eaau6870. http://dx.doi.org/10.1126/scitranslmed.aau6870.

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Mutations in the GBA1 gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase) represent the most common risk factor for Parkinson’s disease (PD). GCase has been identified as a potential therapeutic target for PD and current efforts are focused on chemical chaperones to translocate mutant GCase into lysosomes. However, for several GBA1-linked forms of PD and PD associated with mutations in LRRK2, DJ-1, and PARKIN, activating wild-type GCase represents an alternative approach. We developed a new small-molecule modulator of GCase called S-181 that increased wild-type GCase activity in iP

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Brunialti, Electra, Alessandro Villa, Marco Toffoli, et al. "Sex-Specific Microglial Responses to Glucocerebrosidase Inhibition: Relevance to GBA1-Linked Parkinson’s Disease." Cells 12, no. 3 (2023): 343. http://dx.doi.org/10.3390/cells12030343.

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Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to s

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Szymańska-Rożek, Paulina, Patryk Lipiński, Grazina Kleinotiene, Paweł Dubiela, and Anna Tylki-Szymańska. "Effects of GBA1 Variants and Prenatal Exposition on the Glucosylsphingosine (Lyso-Gb1) Levels in Gaucher Disease Carriers." International Journal of Molecular Sciences 25, no. 22 (2024): 12021. http://dx.doi.org/10.3390/ijms252212021.

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Gaucher disease (GD) is a lysosomal lipid storage disorder caused by β-glucocerebrosidase (encoded by GBA1 gene) activity deficiency, resulting in the accumulation of glucosylceramide (Gb1) and its deacylated metabolite glucosylsphingosine (lyso-Gb1). Lyso-Gb1 has been studied previously and proved to be a sensitive biomarker, distinguishing patients with GD from carriers and healthy subjects. It was shown that its level corresponds with β-glucocerebrosidase activity, thus it remains unknown as to why carriers have slightly higher lyso-Gb1 level than healthy population. This is the first repor

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Dubiela, Paweł, Paulina Szymańska-Rożek, Andrzej Eljaszewicz, et al. "Alpha-Synuclein mRNA Level Found Dependent on L444P Variant in Carriers and Gaucher Disease Patients on Enzyme Replacement Therapy." Biomolecules 13, no. 4 (2023): 644. http://dx.doi.org/10.3390/biom13040644.

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Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for β-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson’s disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosi

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Perez-Abshana, Laura Patricia, Miguel Mendivil-Perez, Marlene Jimenez-Del-Rio, and Carlos Velez-Pardo. "The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts." International Journal of Molecular Sciences 25, no. 17 (2024): 9220. http://dx.doi.org/10.3390/ijms25179220.

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Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 (GBA1) gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks

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Yang, Chunzhang, Herui Wang, Dongwang Zhu, et al. "Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation." Proceedings of the National Academy of Sciences 112, no. 4 (2015): 1137–42. http://dx.doi.org/10.1073/pnas.1424288112.

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Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced G

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Montpeyo, Marta, Natàlia Pérez-Carmona, Elena Cubero, et al. "Developing Allosteric Chaperones for GBA1-Associated Disorders—An Integrated Computational and Experimental Approach." International Journal of Molecular Sciences 26, no. 1 (2024): 9. https://doi.org/10.3390/ijms26010009.

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Mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are associated with Gaucher disease and increased risk of Parkinson’s disease. This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived

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Bezrukova, Anastasia I., Katerina S. Basharova, Galina V. Baydakova, Ekaterina Y. Zakharova, Sofya N. Pchelina, and Tatiana S. Usenko. "Dose-Dependent Alterations of Lysosomal Activity and Alpha-Synuclein in Peripheral Blood Monocyte-Derived Macrophages and SH-SY5Y Neuroblastoma Cell Line by upon Inhibition of MTOR Protein Kinase – Assessment of the Prospects of Parkinson’s Disease Therapy." Biochemistry (Moscow) 89, no. 7 (2024): 1300–1312. http://dx.doi.org/10.1134/s0006297924070113.

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Abstract To date, the molecular mechanisms of the common neurodegenerative disorder Parkinson’s disease (PD) are unknown and, as a result, there is no neuroprotective therapy that may stop or slow down the process of neuronal cell death. The aim of the current study was to evaluate the prospects of using the mTOR molecule as a potential target for PD therapy due to the dose-dependent effect of mTOR kinase activity inhibition on cellular parameters associated with, PD pathogenesis. The study used peripheral blood monocyte-derived macrophages and SH-SY5Y neuroblastoma cell line. As a result, we

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Franco, Valentina, Michela Palmisani, Fabiana Colucci, et al. "LC-MS/MS-Based Determination of Ambroxol in Human Plasma and Cerebrospinal Fluid: Validation and Applicability in Phase II Study on GBA-Associated Parkinson’s Disease Patients." International Journal of Molecular Sciences 26, no. 13 (2025): 6094. https://doi.org/10.3390/ijms26136094.

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Heterozygous mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase (GCase), are major risk factors for Parkinson’s Disease (PD). Ambroxol, a small chaperone originally used as a mucolytic agent, has been shown to cross the blood–brain barrier, enhance glucocerebrosidase activity, and reduce α-synuclein levels, making it a promising therapeutic candidate for disease-modifying effects in GBA1-associated PD (GBA1-PD). This study aimed to develop a method to quantify ambroxol levels in human plasma and cerebrospinal fluid (CSF) using liquid chromatography–tandem mass spectrometry (LC-

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Dr. Alisha Naaz, Dr Alisha Naaz, Dr Afsha Anjum Dr. Afsha Anjum, Dr Pranju Aswal, and Anas Khan. "Gaucher Disease Unveiled: From Genes to Targeted Therapy." International Journal of Pharmaceutical Research and Applications 10, no. 3 (2025): 1951–58. https://doi.org/10.35629/4494-100319511958.

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Gaucher disease (GD), an autosomal recessive lysosomal storage disorder first described by Philippe Gaucher in 1882, results from mutations in the GBA1 gene, leading to deficient glucocerebrosidase activity and subsequent accumulation of glucocerebroside in macrophages. This causes multisystem involvement, primarily affecting the liver, spleen, and bone marrow. With an incidence of 1:40,000-60,000 globally, GD shows ethnic variability, being more prevalent among Ashkenazi Jews (1:850). Type 1 (nonneuronopathic) accounts for 90% of cases, while types 2 and 3 (neuronopathic) and rare perinatal/c

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Do, Jenny, Gani Perez, Bahafta Berhe, Nahid Tayebi, and Ellen Sidransky. "Behavioral Phenotyping in a Murine Model of GBA1-Associated Parkinson Disease." International Journal of Molecular Sciences 22, no. 13 (2021): 6826. http://dx.doi.org/10.3390/ijms22136826.

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Mutations in GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled GBA1-associated PD by crossing gba haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (SNCAA53T), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether gba+/−//SNCAA53T mi

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Zuckerman, Shachar, Ari Zimran, Jeff Szer, Shoshana Revel-Vilk, and Gheona Altarescu. "Preimplantation Genetic Testing (PGT) to Reduce the Risk for GBA-Related Parkinson’s Disease: Expanding the Applications for Embryo Selection." International Journal of Molecular Sciences 26, no. 3 (2025): 912. https://doi.org/10.3390/ijms26030912.

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Preimplantation genetic testing (PGT) is practiced worldwide, allowing the prevention of the transmission and expression of various genetic conditions. Socio-ethical considerations of justified applications for PGT are part of an ongoing debate. Pathogenic variants in the glucocerebrosidase (GBA1) gene, causing Gaucher disease (GD), have emerged as a risk factor for Parkinson’s disease (PD) in both patients and carriers. Genotype–phenotype correlations exist between different GBA1 pathogenic variants and the risk to develop PD: mild pathogenic variants increase the risk of developing PD by ~3-

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Qi, Wenduo, Brad A. Davidson, Matthew Nguyen, et al. "Validation of anti-glucocerebrosidase antibodies for western blot analysis on protein lysates of murine and human cells." Biochemical Journal 476, no. 2 (2019): 261–74. http://dx.doi.org/10.1042/bcj20180708.

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Abstract Gaucher disease (GD) is a rare lysosomal storage disorder caused by mutations in the GBA1 gene, encoding the lysosome-resident glucocerebrosidase enzyme involved in the hydrolysis of glucosylceramide. The discovery of an association between mutations in GBA1 and the development of synucleinopathies, including Parkinson disease, has directed attention to glucocerebrosidase as a potential therapeutic target for different synucleinopathies. These findings initiated an exponential growth in research and publications regarding the glucocerebrosidase enzyme. The use of various commercial an

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Istaiti, Majdolen, Gilad Yahalom, Mikhal Cohen, et al. "Sidransky Syndrome—GBA1-Related Parkinson’s Disease and Its Targeted Therapies." International Journal of Molecular Sciences 26, no. 7 (2025): 3435. https://doi.org/10.3390/ijms26073435.

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Sidransky syndrome represents a distinct variant of Parkinson’s disease (PD) that is linked to pathogenic variants in the glucocerebrosidase (GBA1) gene. This disorder exhibits an earlier onset, a more severe course, and a higher dementia prevalence compared to idiopathic PD. While the pathogenesis remains debated between loss-of-function and gain-of-function mechanisms, targeted therapies are emerging. Pharmacological chaperones (PCs), like high-dose Ambroxol, aim to mitigate enzyme misfolding—a primary driver of this disorder—rather than addressing metabolic deficiencies seen in Gaucher dise

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Minakaki, Georgia, Nathaniel Safren, Bernabe I. Bustos, Steven J. Lubbe, Niccolò E. Mencacci, and Dimitri Krainc. "Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk." Science 388, no. 6743 (2025): 204–11. https://doi.org/10.1126/science.adq6650.

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Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain–containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain–containing protein 22 (CCDC22)/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity. Loss of COMMD3 incr

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Shechter, Yosef, Mikhal Cohen, Gilad Yahalom, et al. "Contrasting olfactory perception in Parkinson disease: Impact of GBA1 gene mutations." Molecular Genetics and Metabolism 144, no. 2 (2025): 108946. https://doi.org/10.1016/j.ymgme.2024.108946.

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Fregno, Ilaria, Natalia Pérez-Carmona, Mikhail Rudinskiy, et al. "Allosteric Modulation of GCase Enhances Lysosomal Activity and Reduces ER Stress in GCase-Related Disorders." International Journal of Molecular Sciences 26, no. 9 (2025): 4392. https://doi.org/10.3390/ijms26094392.

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Variants in the GBA1 gene, encoding the lysosomal enzyme glucosylceramidase beta 1 (GCase), are linked to Parkinson’s disease (PD) and Gaucher disease (GD). Heterozygous variants increase PD risk, while homozygous variants lead to GD, a lysosomal storage disorder. Some GBA1 variants impair GCase maturation in the endoplasmic reticulum, blocking lysosomal transport and causing glucosylceramide accumulation, which disrupts lysosomal function. This study explores therapeutic strategies to address these dysfunctions. Using Site-directed Enzyme Enhancement Therapy (SEE-Tx®), two structurally target

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Mokhtar, Abdullah Alkhalaf et al. "Gaucher Disease: A Comprehensive Review." International Journal of Scientific Research and Innovative Studies 3, no. 6 (2024): 49–52. https://doi.org/10.5281/zenodo.14260224.

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Abstract Gaucher disease (GD) is a rare lysosomal storage disorder caused by mutations in the <em>GBA1</em> gene, which encodes the enzyme glucocerebrosidase. This deficiency results in the accumulation of glucocerebroside in macrophages, leading to multi-organ involvement. GD manifests in three main types, each with distinct clinical features. Recent advancements in enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and novel treatment strategies such as gene therapy have improved patient outcomes significantly. This review explores the pathophysiology, clinical manifestatio

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Jarmołowicz, Jakub, Paulina Krzeszowska, Aleksandra Kujawa, et al. "Gaucher's disease - a review of the most important information about the disease in Paediatrics." Quality in Sport 43 (July 12, 2025): 61358. https://doi.org/10.12775/qs.2025.43.61358.

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Gaucher disease is an autosomal recessive spirochete disease caused by a deficiency of the enzyme glucocerebrosidase. A mutation in the GBA1 gene induces the accumulation of abnormal products in macrophages resulting in the transformation into Gaucher cells in many organs. There are three main types of the disease, 1 being the most common type (non-neuropathic). The 2nd and 3rd types of the disease are neuropathic types and these occur mainly in childhood. Among paediatric patients, Gaucher's disease manifests mainly with enlargement of the liver, spleen, thrombocytopenia, anaemia, but skeleta

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Canbek, Sezin, Goncagül Mert, Muhammed Fatih Gülseven, and Mehmet Güney Şenol. "GBA1 variants and Parkinson’s Disease: A dual approach combining clinical data and literature review." Ege Tıp Dergisi 64, no. 2 (2025): 231–42. https://doi.org/10.19161/etd.1583422.

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Background: The GBA gene, a key susceptibility gene in Parkinson’s disease (PD) and closely linked to Gaucher disease, has garnered significant research attention over the past two decades. Mutations in GBA are associated with an elevated risk of developing PD. This study aims to elucidate the genetic mutations related to PD in a cohort of patients undergoing clinical exome analysis. Objective: To investigate the clinical and genetic profiles of patients with Parkinson’s disease, focusing on GBA gene mutations and additional neurodegenerative-related genetic alterations. Methods: Fourteen pati

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Blokhin, Victor, Maria Shupik, Ulyana Gutner, et al. "The Sphingolipid Asset Is Altered in the Nigrostriatal System of Mice Models of Parkinson’s Disease." Biomolecules 12, no. 1 (2022): 93. http://dx.doi.org/10.3390/biom12010093.

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Parkinson’s disease (PD) is a neurodegenerative disease incurable due to late diagnosis and treatment. Therefore, one of the priorities of neurology is to study the mechanisms of PD pathogenesis at the preclinical and early clinical stages. Given the important role of sphingolipids in the pathogenesis of neurodegenerative diseases, we aimed to analyze the gene expression of key sphingolipid metabolism enzymes (ASAH1, ASAH2, CERS1, CERS3, CERS5, GBA1, SMPD1, SMPD2, UGCG) and the content of 32 sphingolipids (subspecies of ceramides, sphingomyelins, monohexosylceramides and sphinganine, sphingosi

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Bezrukova, A. I., K. S. Basharova, G. V. Baydakova, E. Y. Zakharova, S. N. Pchelina, and T. S. Usenko. "Dose-Dependent Alterations of Lysosomal Activity and Alpha-Synuclein in Peripheral Blood Monocyte-Derived Macrophages and SH-SY5Y Neuroblastoma Cell Line by upon Inhibition of mTOR Protein Kinase – Assessment of the Prospects of Parkinson’s Disease Therapy." Biohimiâ 89, no. 7 (2024): 1248–62. https://doi.org/10.31857/s0320972524070085.

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To date, the molecular mechanisms of the common neurodegenerative disorder Parkinson’s disease (PD) are unknown and, as a result, there is no neuroprotective therapy that may stop or slow down the process of neuronal cell death. The aim of the current study was to evaluate the prospects of using the mTOR molecule as a potential target for PD therapy due dose-dependent effect of mTOR kinase activity inhibition on cellular parameters, the alteration of which is associated with pathogenesis of the PD. The study was performed on peripheral blood monocyte-derived macrophages and SH-SY5Y neuroblasto

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Heijer, Jonas M., Valerie C. Cullen, Marialuisa Quadri, et al. "A Large‐Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands." Movement Disorders 35, no. 9 (2020): 1667–74. http://dx.doi.org/10.1002/mds.28112.

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Nakanishi, Etsuro, Norihito Uemura, Hisako Akiyama та ін. "Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes)". Molecular Brain 14, № 1 (2021). http://dx.doi.org/10.1186/s13041-021-00790-x.

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AbstractHomozygous mutations in the lysosomal glucocerebrosidase gene, GBA1, cause Gaucher’s disease (GD), while heterozygous mutations in GBA1 are a strong risk factor for Parkinson’s disease (PD), whose pathological hallmark is intraneuronal α-synuclein (asyn) aggregates. We previously reported that gba1 knockout (KO) medaka exhibited glucosylceramide accumulation and neuronopathic GD phenotypes, including short lifespan, the dopaminergic and noradrenergic neuronal cell loss, microglial activation, and swimming abnormality, with asyn accumulation in the brains. A recent study reported that d

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Lagas, Joseph S., Monica F. Sentmanat, and Xiaoxia Cui. "Efficient GBA1 editing via HDR with ssODNs by outcompeting pseudogene-mediated gene conversion upon CRISPR/Cas9 cleavage." Frontiers in Genome Editing 7 (April 30, 2025). https://doi.org/10.3389/fgeed.2025.1581743.

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IntroductionCRISPR/Cas9-edited induced pluripotent stem cells (iPSCs) are valuable research models for mechanistic studies. However, gene conversion between a gene-pseudogene pair that share high sequence identity and form direct repeats in proximity on the same chromosome can interfere with the precision of gene editing. Mutations in the human beta-glucocerebrosidase gene (GBA1) are associated with Gaucher disease, Parkinson’s disease, and Lewy body dementia. During the creation of a GBA1 KO iPSC line, we detected about 70% gene conversion from its pseudogene GBAP1. These events maintained th

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