Affinage

GBA1

Lysosomal acid glucosylceramidase · UniProt P04062

Length
536 aa
Mass
59.7 kDa
Annotated
2026-06-10
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GBA1 encodes lysosomal glucocerebrosidase (GCase), which hydrolyzes the glycolipid glucocerebroside to ceramide and glucose; loss-of-function mutations cause lysosomal storage of glucocerebroside and underlie Gaucher disease, with nearly 300 characterized variants including complex alleles arising from recombination with the GBAP1 pseudogene (PMID:18338393). Pathogenic missense alleles disrupt GCase through variant-specific routes: severe mutations such as N370S and L444P drive ER retention of misfolded enzyme, activating ER stress and the unfolded protein response, fragmenting the Golgi, and impairing autophagy and lysosomal function, with downstream mitochondrial damage and cell death (PMID:28779532, PMID:38641924). Loss of GCase activity produces accumulation of its substrates glucosylceramide and glucosylsphingosine and a broader sphingolipid dyshomeostasis (PMID:31751314, PMID:35362022), and this lipid imbalance directly accelerates α-synuclein aggregation kinetics in vitro (PMID:35362022); the milder E326K risk variant promotes insoluble α-synuclein and lipid-droplet accumulation without measurable enzyme loss or ER stress, defining a distinct lipid-centric mechanism (PMID:36130205). GCase deficiency impairs proteostasis through mutation-specific degradation defects — severe alleles block macroautophagy and CMA differently — leading to accumulation of both α-synuclein and tau, reversible by the GCase chaperone ambroxol (PMID:35179198, PMID:38641924). In patient-derived midbrain neurons and organoids, reduced GCase drives α-synuclein into Lewy-body-like fibrillar inclusions with seeding activity and accelerates dopaminergic vulnerability, with genetic or pharmacological restoration of GCase or α-synuclein removal providing rescue (PMID:29310663, PMID:39570889). GCase deficiency also dysregulates mitochondrial quality control, including prolonged mitochondria–lysosome contacts via defective TBC1D15/Rab7-mediated untethering (PMID:33753743, PMID:31751314), impairs oligodendrocyte myelination (PMID:38454456), and engages cell-type-specific crosstalk with LRRK2 in astrocytes and with progranulin as a pathway modifier (PMID:32034799, PMID:36574647). GBA1 expression is controlled upstream by a SATB1–miR-22 axis (PMID:38303548), and an African-ancestry noncoding variant disrupts an intronic branchpoint to cause intron retention and reduce functional GCase (PMID:39668204).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2008 High

    Established the core biochemical identity of GBA1 as lysosomal glucocerebrosidase and catalogued the loss-of-function mutation spectrum that causes Gaucher disease, framing the gene as an enzyme whose mutations span every functional class.

    Evidence Comprehensive mutation-function review with structural annotation of ~300 variants and pseudogene recombination characterization

    PMID:18338393

    Open questions at the time
    • Does not address how individual mutations differ mechanistically beyond enzyme loss
    • Connection to neurodegeneration not yet established
  2. 2017 Medium

    Showed that the severe N370S allele acts not merely by reducing catalysis but by retaining misfolded enzyme in the ER, linking GBA1 mutation to ER stress, UPR, Golgi fragmentation, autophagy impairment, and mitochondrial damage.

    Evidence Multi-modal imaging, cholesterol staining, EM, and flow cytometry in N370S/WT patient fibroblasts

    PMID:28779532

    Open questions at the time
    • Single patient-derived cell type
    • Does not show how ER retention couples to downstream α-synuclein pathology
  3. 2018 Medium

    Defined dual mechanisms by which the L444P allele disrupts mitochondrial quality control — impeding mitophagy priming/autophagy induction independently of lysosomal activity while genetic loss blocks autophagic cargo clearance — and demonstrated that GBA-driven α-synuclein accumulation renders dopaminergic neurons vulnerable, rescued by SNCA knockout or GBA overexpression.

    Evidence L444P knockin mice, SH-SY5Y overexpression/depletion, MPTP challenge, SNCA-/- and AAV-GBA rescue, human PD tissue

    PMID:29310663 PMID:30160596

    Open questions at the time
    • Mechanism of activity-independent mitophagy block not molecularly resolved
    • Single-lab in vivo models
  4. 2018 Medium

    Demonstrated in vivo that reduced GBA1 activity accelerates synucleinopathy progression, establishing a genetic interaction between GBA1 deficiency and α-synuclein toxicity.

    Evidence D409H GBA1 knockin × A53T α-synuclein transgenic double-mutant mice with neuropathological and behavioral readouts

    PMID:29703245

    Open questions at the time
    • Does not isolate enzyme loss from misfolding contributions
    • Mechanism linking GCase loss to aggregation not addressed here
  5. 2019 Medium

    Connected substrate accumulation (glucosylceramide, glucosylsphingosine) to impaired clearance of depolarized mitochondria with compensatory TFEB/PGC1α induction, placing mitochondrial quality control downstream of GCase deficiency.

    Evidence 3D neurosphere model with hetero/homozygous GBA mutations, CCCP mitophagy, autophagy flux assays

    PMID:31751314

    Open questions at the time
    • Compensatory transcriptional response not functionally validated
    • Single model system
  6. 2020 Medium

    Revealed cell-type-specific GBA1 biology in astrocytes and functional crosstalk with LRRK2, showing lysosomal and inflammatory deficits normalized by LRRK2 kinase inhibition.

    Evidence D409V knockin mouse astrocytes, lysosomal assays, TLR4-stimulated cytokine analysis, LRRK2 inhibitor rescue

    PMID:32034799

    Open questions at the time
    • Molecular basis of GBA1–LRRK2 crosstalk undefined
    • Single lab
  7. 2021 High

    Identified a specific organelle-contact mechanism: GCase deficiency prolongs mitochondria–lysosome contacts through defective TBC1D15-mediated Rab7 GTP hydrolysis, with rescue by GCase modulation or TBC1D15 overexpression.

    Evidence Patient iPSC-derived midbrain dopaminergic neurons, live-cell contact imaging, GCase activity assays, genetic and pharmacological rescue

    PMID:33753743

    Open questions at the time
    • How reduced GCase activity mechanistically impairs TBC1D15 function unresolved
  8. 2022 High

    Distinguished mechanistically divergent variants — L444P drives sphingolipid remodeling that directly accelerates α-synuclein aggregation in vitro, whereas E326K promotes insoluble α-synuclein and lipid droplets without enzyme loss or ER stress — establishing lipid dyshomeostasis as a unifying yet variant-specific driver, with ambroxol rescue for L444P.

    Evidence Shotgun lipidomics, recombinant α-synuclein aggregation kinetics, fibril lipidomics, E326K/L444P fibroblast and SH-SY5Y lines, ambroxol rescue

    PMID:35362022 PMID:36130205

    Open questions at the time
    • Causal lipid species not definitively isolated
    • E326K lipid-droplet mechanism not linked to aggregation pathway
  9. 2022 Medium

    Extended GBA1 proteostasis dysfunction beyond α-synuclein to tau in cholinergic neurons, and identified progranulin (GRN) as a functional GBA1 pathway modifier amenable to peptide-based rescue.

    Evidence N370S patient-derived cholinergic neurons with ambroxol rescue; Grn KO × Gba9v/9v double-mutant mice with ND7 peptide rescue

    PMID:35179198 PMID:36574647

    Open questions at the time
    • Mechanism linking GCase to tau proteostasis undefined
    • PGRN–GCase molecular interaction not resolved
  10. 2024 Medium

    Resolved that mild versus severe GBA1 mutations cause α-synuclein accumulation through distinct degradation defects — severe alleles block macroautophagy and trigger oligomer secretion, while N370S selectively impairs CMA of monomeric α-synuclein.

    Evidence iPSC-derived dopaminergic neurons across N370S, L444P, D409H variants; autophagosome formation/fusion, CMA, oligomer ELISA and secretion assays

    PMID:38641924

    Open questions at the time
    • Single lab
    • Does not establish which defect dominates in patient brain
  11. 2024 Medium

    Expanded GBA1 biology beyond neurons to oligodendrocytes, showing GCase activity is required for myelination and prevention of demyelination, axonal degeneration, and α-synuclein accumulation.

    Evidence Oligodendrocyte-specific Gba1 conditional knockout mice and Oli-neu CBE inhibitor model with lipidomics and differentiation assays

    PMID:38454456

    Open questions at the time
    • Lipid species driving myelination defect not pinpointed
    • Single lab
  12. 2024 Medium

    Defined upstream transcriptional control of GBA1 via a SATB1–miR-22 axis and showed glucocerebroside accumulation alone is sufficient to induce a senescence-like phenotype in dopaminergic neurons.

    Evidence Neuronal lines, iPSC-derived dopaminergic neurons and mice; SATB1 knockdown, miR-22 manipulation, GluCer quantification, senescence markers

    PMID:38303548

    Open questions at the time
    • Direct miR-22 binding to GBA1 transcript not detailed here
    • Relevance of senescence to PD progression unestablished
  13. 2024 High

    Established a noncoding splicing mechanism for an African-ancestry risk variant — rs3115534 disrupts an intron 8 branchpoint causing non-coding intron-retained transcripts and dose-dependent GCase reduction — and revealed unannotated brain GBA1 isoforms lacking the lysosomal targeting domain plus pervasive GBAP1 read confounding.

    Evidence Full-length and long-read RNA sequencing, snRNA-seq, proteomics, CRISPR editing, and GCase activity assays across genotypes in human brain and carriers

    PMID:38924406 PMID:39668204

    Open questions at the time
    • Function of nonlysosomal GBA1 isoforms uncharacterized
    • Whether intron-retained transcript has any cellular role unknown
  14. 2025 Medium

    Demonstrated in human midbrain organoids that ER retention of mutant GCase and elevated glucosylceramide are determinants of fibrillar, seeding-competent α-synuclein inclusions, with GCase modulators reducing pathology.

    Evidence GBA1-PD patient iPSC-derived midbrain organoids, ER retention staining, GluCer quantification, α-synuclein seeding/propagation assay, ambroxol/GZ667161 rescue

    PMID:39570889

    Open questions at the time
    • Single lab
    • Relative contributions of ER retention versus substrate accumulation not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what the nonlysosomal, brain-translated GBA1 isoforms lacking the lysosomal targeting domain actually do, and how the diverse variant-specific mechanisms (ER stress, lipid dyshomeostasis, autophagy/CMA defects, organelle-contact dysregulation) are quantitatively integrated to determine neurodegenerative outcome.
  • No functional assignment for nonlysosomal isoforms
  • No unified model weighting competing pathogenic mechanisms
  • Substrate-of-aggregation lipid species not definitively identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005764 lysosome 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-9612973 Autophagy 4 R-HSA-1430728 Metabolism 3
Partners
GRNLRRK2RAB7TBC1D15

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 GBA1 encodes glucocerebrosidase, a lysosomal enzyme that catalyzes the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose; loss-of-function mutations cause lysosomal storage of glucocerebroside in reticuloendothelial cells leading to Gaucher disease. Nearly 300 unique mutations spanning the gene have been characterized, including missense, nonsense, frameshift, splice-junction mutations, and complex alleles from recombination with the downstream pseudogene GBAP1. Mutation spectrum review with structural/functional annotation of ~300 GBA variants; recombination events with pseudogene characterized Human mutation High 18338393
2017 The N370S GBA1 mutation causes ER retention of β-glucocerebrosidase-1 protein, preventing its trafficking to the lysosome, activating ER stress and the unfolded protein response, triggering Golgi fragmentation, impairing autophagy, and causing lysosomal dysfunction with cholesterol accumulation. This results in mitochondrial damage and increased cell death in patient-derived fibroblasts. Western blot, immunofluorescence, LysoTracker, Filipin staining (cholesterol), electron microscopy, flow cytometry (apoptosis, ROS, mitochondrial membrane potential) in PD patient-derived N370S/WT fibroblasts Movement disorders : official journal of the Movement Disorder Society Medium 28779532
2018 The L444P heterozygous GBA1 mutation triggers mitochondrial dysfunction by inhibiting two steps critical for mitophagy: mitochondrial priming and autophagy induction. Overexpression of L444P GBA impeded mitochondrial priming and autophagy induction even when endogenous lysosomal GBA activity was intact, whereas genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo, suggesting dual mechanisms. GbaL444P/WT knockin mice, SH-SY5Y neuroblastoma cells with L444P GBA overexpression, GBA genetic depletion, mitochondrial markers (MitoTracker, TIMM23, TOMM20), LC3B lipidation assay, ROS measurements, postmortem PD brain tissue analysis Autophagy Medium 30160596
2018 L444P GBA heterozygous mutation reduces GBA protein levels and enzymatic activity with concomitant α-synuclein accumulation in the midbrain. α-synuclein knockout or AAV5-mediated GBA overexpression each rescued MPTP-induced dopaminergic neuron loss and motor deficits, establishing that GBA deficiency-driven α-synuclein accumulation renders dopaminergic neurons more susceptible to mitochondrial toxin MPTP. GBA+/L444P knockin mice, SNCA-/- mice, AAV5-hGBA injection, MPTP neurotoxin treatment, immunohistochemistry, HPLC for dopamine metabolites, behavioral tests, mitochondrial morphology/functional assays, Western blot Molecular neurodegeneration Medium 29310663
2018 D409H GBA1 mutation markedly accelerates α-synuclein pathology in A53T α-synuclein transgenic mice: it exacerbates insoluble α-synuclein aggregate formation, glial activation, neuronal degeneration, motor abnormalities, and causes loss of dopaminergic neurons in the substantia nigra. This establishes that GBA1 enzyme activity reduction accelerates synucleinopathy progression. D409H GBA1 knockin × A53T α-synuclein transgenic double-mutant mice; survival analysis, immunohistochemistry, biochemical fractionation for insoluble α-synuclein, motor behavioral testing Acta neuropathologica communications Medium 29703245
2021 GBA1-mutant (heterozygous) patient-derived neurons exhibit prolonged mitochondria-lysosome contacts due to defective modulation of the untethering protein TBC1D15, which mediates Rab7 GTP hydrolysis required for contact untethering. This dysregulation was caused by decreased GBA1 lysosomal enzyme activity and resulted in disrupted mitochondrial distribution and function; restoring GCase activity with a modulator or overexpressing TBC1D15 rescued these defects. Patient iPSC-derived midbrain dopaminergic neurons, live-cell imaging of mitochondria-lysosome contacts (soma, axons, dendrites), GCase activity assay, TBC1D15 rescue overexpression, GCase modulator treatment Nature communications High 33753743
2020 GBA1 D409V knockin astrocytes exhibit broad lysosomal morphology and functional deficits and dramatically impaired basal and TLR4-dependent cytokine production. Both lysosomal dysfunction and inflammatory responses were normalized by LRRK2 kinase inhibition, demonstrating functional crosstalk between GBA1 and LRRK2 in astrocytes. Heterozygous and homozygous D409V GBA1 knockin mouse astrocytes; biochemical and image-based lysosomal assays, cytokine transcriptional and secretory analyses (basal and TLR4-stimulated), LRRK2 kinase inhibitor treatment Movement disorders : official journal of the Movement Disorder Society Medium 32034799
2022 L444P GBA1 mutation produces an altered membrane sphingolipid profile in patient fibroblasts—overall elevated sphingolipids with a shift toward shorter-chain ceramide, sphingomyelin, and hexosylceramide—that directly accelerates α-synuclein aggregation kinetics in vitro. Ambroxol treatment restored glucocerebrosidase activity, normalized sphingolipid composition, and reversed the pro-aggregation effect, establishing a mechanistic link between GCase loss-of-function, lipid dyshomeostasis, and α-synuclein aggregation. Shotgun lipidomics of L444P GBA fibroblasts; recombinant α-synuclein aggregation kinetics assay with lipid extracts; lipidomics of resulting fibrils; ambroxol pharmacological rescue Brain : a journal of neurology High 35362022
2022 The E326K GBA variant does not cause significant loss of GCase protein or activity, ER retention, or ER stress (in contrast to L444P), yet still leads to increased insoluble α-synuclein aggregates. Additionally, E326K causes a significant increase in lipid droplet number under basal conditions and following oleic acid loading, indicating a distinct, lipid-dyshomeostasis mechanism for this risk variant. Homozygous and heterozygous E326K human fibroblasts; E326K and L444P SH-SY5Y overexpression lines; GCase activity/protein assays, ER stress markers, α-synuclein solubility fractionation, lipid droplet staining and quantification with/without oleic acid Human molecular genetics Medium 36130205
2022 N370S GBA1 mutation in cholinergic neurons reduces GCase protein and activity and cathepsin D levels, and significantly increases both tau and α-synuclein protein levels. Ambroxol, a GCase chaperone, enhanced GCase activity and reversed tau and α-synuclein accumulation, establishing that GBA1 dysfunction impairs proteostasis of both α-synuclein and tau in cholinergic neurons. Neural crest stem cell-derived cholinergic neurons from N370S/WT PD patients; GCase activity assay, Western blot for GCase/cathepsin D/tau/α-synuclein, ambroxol treatment rescue Human molecular genetics Medium 35179198
2024 Severe GBA1 mutations (L444P, D409H) increase ER stress and total ubiquitination, impair macroautophagy (L444P blocks autophagosome-lysosome fusion; N370S and D409H reduce autophagosome formation), and trigger accumulation and secretion of oligomeric α-synuclein. Mild mutation N370S specifically impairs chaperone-mediated autophagy (CMA) of monomeric α-synuclein. Thus, mild and severe GBA1 mutations cause α-synuclein accumulation through distinct proteostasis mechanisms. iPSC-derived dopaminergic neurons with N370S (mild), L444P and D409H (severe) GBA1 mutations; ER stress markers, ubiquitination assays, autophagosome formation/fusion assays, CMA activity, oligomeric α-synuclein ELISA and secretion assays Journal of neurochemistry Medium 38641924
2024 GBA1 inactivation in oligodendrocytes (Cnp1-cre × loxP-Gba1 exons 9-11 flox) induces lysosomal dysfunction and inhibits myelination in vitro, and causes in vivo demyelination, axonal degeneration, α-synuclein accumulation, astrogliosis, brain lipid dyshomeostasis and functional impairment, establishing that oligodendrocyte GCase activity is required for myelination and prevention of early neurodegenerative features. Oligodendrocyte-specific Gba1 conditional knockout mice (Cnp1-cre × loxP-Gba1); Oli-neu myelination induction model with CBE inhibitor; immunofluorescence, Western blot, lipidomics, primary oligodendrocyte culture differentiation assays Molecular neurodegeneration Medium 38454456
2019 GBA1 encodes glucocerebrosidase, and loss of its activity causes accumulation of its glycolipid substrates glucosylceramide and glucosylsphingosine. GBA mutation promotes mitochondrial accumulation and impaired clearance of depolarized mitochondria in GBA-mutant neurospheres (heterozygous and homozygous), with compensatory upregulation of TFEB and PGC1α mRNA, indicating impaired mitochondrial quality control downstream of GCase deficiency. 3D neurosphere model from neural crest stem cells with heterozygous and homozygous GBA mutations; CCCP-induced mitophagy; mitochondrial content/function markers, ATP levels, TFEB and PGC1α mRNA quantification, macroautophagy flux assay Aging Medium 31751314
2024 An African ancestry-specific noncoding GBA1 risk variant (rs3115534-G) disrupts an intronic branchpoint sequence in intron 8, causing retention of a partial intron 8 in transcripts. This intron-retained isoform is not protein-coding (confirmed by N-terminal antibody staining and proteomics). CRISPR editing of rs3115534 confirmed it drives aberrant splicing. Risk variant carriers show a dose-dependent reduction in glucocerebrosidase activity, establishing that this noncoding variant reduces functional GBA1 protein through a splicing mechanism. Full-length RNA transcript sequencing in risk variant vs. non-variant carriers; N-terminal GCase antibody immunoblot; proteomics; CRISPR editing of rs3115534; glucocerebrosidase activity assay across genotypes Nature structural & molecular biology High 39668204
2012 GBA2 (non-lysosomal β-glucosidase) enzymatic activity accounts for over 85% of total brain GBA activity in wild-type mice, and is significantly elevated in GBA1-deficient mice brains compared to heterozygotes and wild-types. Some Gaucher disease patients also show markedly elevated GBA2 activity in leukocytes, suggesting a compensatory upregulation of GBA2 in response to GBA1 deficiency. Enzymatic activity assays for GBA1 and GBA2 in brain tissue from wild-type, heterozygous, and GBA1-deficient mice; GBA2 activity assay in leukocytes from 13 Gaucher patients, 10 heterozygotes, and 19 controls Journal of inherited metabolic disease Medium 23151684
2017 GBA1 (Gba1a ortholog) was identified in a signalome-wide RNAi screen as a mediator of autophagic cell death. Knockdown of Gba1a in two independent Drosophila RNAi lines delayed developmental midgut cell death during metamorphosis, establishing that GBA1 is a conserved critical regulator of autophagy levels required for autophagic cell death. RNAi screen in human lung carcinoma cells (resveratrol-induced autophagic death); two independent Gba1a RNAi lines in Drosophila midgut; morphological analysis of midgut regression during metamorphosis Cell cycle (Georgetown, Tex.) Medium 28933588
2024 Downregulation of the transcriptional repressor SATB1 leads to derepression of miR-22-3p, which reduces GBA1 expression and causes glucocerebroside accumulation. This GluCer increase alone is sufficient to impair lysosomal and mitochondrial function, inducing a cellular senescence-like phenotype in dopaminergic neurons. The SATB1–miR-22–GBA1 regulatory axis was dysregulated in PD patients and normal aging. Human and murine neuronal lines, iPSC-derived dopaminergic neurons, and mice; SATB1 knockdown, miR-22-3p manipulation, GBA expression measurement, GluCer quantification, lysosomal/mitochondrial function assays, senescence markers Aging cell Medium 38303548
2025 In iPSC-derived midbrain organoids from GBA1-PD patients, retention of mutant glucocerebrosidase in the ER and elevated glucosylceramide levels are determinants of α-synuclein aggregation into Lewy body-like inclusions with fibrillary structure and seeding activity. Reduction of GCase activity accelerated fibrillary α-synuclein deposition. Ambroxol and GZ667161 (GCase modulators) reduced α-synuclein pathology in this model. Patient iPSC-derived midbrain organoids; ER retention immunostaining, glucosylceramide quantification, α-synuclein seeding assay (propagation to healthy organoids), ambroxol/GZ667161 pharmacological rescue Brain : a journal of neurology Medium 39570889
2022 PGRN (progranulin, encoded by GRN) is a modifier of GCase (GBA1): PGRN deficiency in Gba9v/9v (D409V homozygous) mice exacerbates Gaucher disease phenotypes, neuroinflammation (microgliosis, astrogliosis), impaired autophagy, and PD-like pathology. A PGRN-derived peptide (ND7) that crosses the blood-brain barrier ameliorated neuropathic Gaucher and PD pathology in Gba1-mutant mice, identifying PGRN as a functional GBA1 pathway modifier. Grn KO × Gba9v/9v double-mutant mice; neurobehavioral testing, neuropathology, neuroinflammation markers, autophagy assays; ND7 peptide BBB penetration assay, ex vivo patient fibroblast rescue, in vivo rescue in Gba9v/null and PG9V mice Proceedings of the National Academy of Sciences of the United States of America Medium 36574647
2024 Long-read RNA sequencing in human brain identified currently unannotated GBA1 transcripts, including protein-coding transcripts lacking the known lysosomal targeting domain that account for almost a third of GBA1 transcription, and revealed that >50% of short-read RNA-seq reads from GBA1 also map to the pseudogene GBAP1, indicating previous expression analyses were confounded. This suggests GBA1 has nonlysosomal isoforms translated in the brain. Long-read RNA sequencing (human brain); single-nucleus RNA sequencing; proteomics to confirm translation of novel isoforms; comparison with short-read RNA-seq Science advances Medium 38924406

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Human mutation 508 18338393
2012 The link between the GBA gene and parkinsonism. The Lancet. Neurology 455 23079555
2016 Survival and dementia in GBA-associated Parkinson's disease: The mutation matters. Annals of neurology 323 27632223
2015 Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology 312 25653295
2008 Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 306 18434642
2019 GBA, Gaucher Disease, and Parkinson's Disease: From Genetic to Clinic to New Therapeutic Approaches. Cells 208 31010158
2020 Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. Brain : a journal of neurology 196 31755958
2018 Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy 191 30160596
2022 GBA Variants and Parkinson Disease: Mechanisms and Treatments. Cells 178 35455941
2021 Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson's disease. Nature communications 152 33753743
2020 GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort. Movement disorders : official journal of the Movement Disorder Society 123 32658388
2018 GBA-Associated Parkinson's Disease and Other Synucleinopathies. Current neurology and neuroscience reports 122 29884970
2018 α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism. Molecular neurodegeneration 111 29310663
2022 GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10-Year Population-Based Study. Movement disorders : official journal of the Movement Disorder Society 103 35106798
2017 N370S-GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 97 28779532
2020 Lysosome and Inflammatory Defects in GBA1-Mutant Astrocytes Are Normalized by LRRK2 Inhibition. Movement disorders : official journal of the Movement Disorder Society 87 32034799
2022 Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers. Annals of neurology 84 34984729
2017 Serum lipid alterations in GBA-associated Parkinson's disease. Parkinsonism & related disorders 80 28890071
2017 Molecular mechanisms of α-synuclein and GBA1 in Parkinson's disease. Cell and tissue research 74 29064079
2022 Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation. Brain : a journal of neurology 68 35362022
2021 Cross-talks among GBA mutations, glucocerebrosidase, and α-synuclein in GBA-associated Parkinson's disease and their targeted therapeutic approaches: a comprehensive review. Translational neurodegeneration 67 33446243
2022 LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease. Translational neurodegeneration 64 35101134
2020 GBA Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes. Movement disorders : official journal of the Movement Disorder Society 63 32853481
2021 Gene Therapy for Parkinson's Disease Associated with GBA1 Mutations. Journal of Parkinson's disease 62 34151863
2020 The SPID-GBA study: Sex distribution, Penetrance, Incidence, and Dementia in GBA-PD. Neurology. Genetics 61 33209983
2021 Exploring the Genotype-Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers. Frontiers in neurology 59 34248830
2020 A Large-Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands. Movement disorders : official journal of the Movement Disorder Society 59 32618053
2023 Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues. Pharmacology & therapeutics 51 37080432
2020 Small Molecule Chaperones for the Treatment of Gaucher Disease and GBA1-Associated Parkinson Disease. Frontiers in cell and developmental biology 50 32509770
2017 GBA Analysis in Next-Generation Era: Pitfalls, Challenges, and Possible Solutions. The Journal of molecular diagnostics : JMD 49 28727984
2015 Advances in GBA-associated Parkinson's disease--Pathology, presentation and therapies. Neurochemistry international 49 26743617
2022 Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease. Frontiers in neurology 43 36034282
2020 LRRK2 and GBA Variants Exert Distinct Influences on Parkinson's Disease-Specific Metabolic Networks. Cerebral cortex (New York, N.Y. : 1991) 43 31813991
2019 Evolution and clustering of prodromal parkinsonian features in GBA1 carriers. Movement disorders : official journal of the Movement Disorder Society 43 31251436
2022 GBA-associated PD: chances and obstacles for targeted treatment strategies. Journal of neural transmission (Vienna, Austria : 1996) 42 35639160
2018 A Meta-Analysis of GBA-Related Clinical Symptoms in Parkinson's Disease. Parkinson's disease 42 30363648
2021 Plasma Glucosylsphingosine in GBA1 Mutation Carriers with and without Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society 39 34741486
2024 Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease. Translational neurodegeneration 38 39267121
2023 GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy. Journal of movement disorders 32 37302978
2021 Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: mutational spectrum and clinical features. Journal of neural transmission (Vienna, Austria : 1996) 32 34779914
2021 GBA mutations, glucosylceramide and Parkinson's disease. Current opinion in neurobiology 31 34883387
2023 GBA1 Gene Mutations in α-Synucleinopathies-Molecular Mechanisms Underlying Pathology and Their Clinical Significance. International journal of molecular sciences 30 36768367
2022 Role of Lysosomal Gene Variants in Modulating GBA-Associated Parkinson's Disease Risk. Movement disorders : official journal of the Movement Disorder Society 30 35262230
2018 D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model. Acta neuropathologica communications 30 29703245
2023 A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator. Movement disorders : official journal of the Movement Disorder Society 29 37195859
2014 The significance of GBA for Parkinson's disease. Journal of inherited metabolic disease 29 24894157
2024 GBA1-Associated Parkinson's Disease Is a Distinct Entity. International journal of molecular sciences 27 39000225
2023 The Consequences of GBA Deficiency in the Autophagy-Lysosome System in Parkinson's Disease Associated with GBA. Cells 27 36611984
2023 Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol. BMJ neurology open 27 38027469
2022 Transcriptome deregulation of peripheral monocytes and whole blood in GBA-related Parkinson's disease. Molecular neurodegeneration 26 35978378
2019 Can GBA1-Associated Parkinson Disease Be Modeled in the Mouse? Trends in neurosciences 26 31288942
2012 Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes. Journal of inherited metabolic disease 26 23151684
2024 GBA moderates cognitive reserve's effect on cognitive function in patients with Parkinson's disease. Journal of neurology 25 38656622
2023 The GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines. Human molecular genetics 25 36130205
2020 Common Variants Coregulate Expression of GBA and Modifier Genes to Delay Parkinson's Disease Onset. Movement disorders : official journal of the Movement Disorder Society 25 32557794
2024 The SATB1-MIR22-GBA axis mediates glucocerebroside accumulation inducing a cellular senescence-like phenotype in dopaminergic neurons. Aging cell 24 38303548
2023 Mutational spectrum and clinical features of GBA1 variants in a Chinese cohort with Parkinson's disease. NPJ Parkinson's disease 24 37658046
2018 Cerebral Imaging Markers of GBA and LRRK2 Related Parkinson's Disease and Their First-Degree Unaffected Relatives. Brain topography 24 29846835
2016 Glucocerebrosidase enzyme activity in GBA mutation Parkinson's disease. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 24 26857292
2022 Prevalence and genotype-phenotype correlations of GBA-related Parkinson disease in a large Chinese cohort. European journal of neurology 23 34951095
2021 Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers. Journal of Parkinson's disease 23 33998549
2020 GBA variation and susceptibility to multiple system atrophy. Parkinsonism & related disorders 22 32623306
2023 A Biomarker Study in Patients with GBA1-Parkinson's Disease and Healthy Controls. Movement disorders : official journal of the Movement Disorder Society 21 36916660
2024 Increased glucosylsphingosine levels and Gaucher disease in GBA1-associated Parkinson's disease. Parkinsonism & related disorders 20 38843618
2012 Mutant GBA1 expression and synucleinopathy risk: first insights from cellular and mouse models. Neuro-degenerative diseases 20 22327140
2024 GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice. Molecular neurodegeneration 19 38454456
2023 Inflammatory CSF profiles and longitudinal development of cognitive decline in sporadic and GBA-associated PD. NPJ Parkinson's disease 19 36906614
2023 Unraveling neurotransmitter changes in de novo GBA-related and idiopathic Parkinson's disease. Neurobiology of disease 19 37558169
2022 Ambroxol reverses tau and α-synuclein accumulation in a cholinergic N370S GBA1 mutation model. Human molecular genetics 19 35179198
2019 GBA mutation promotes early mitochondrial dysfunction in 3D neurosphere models. Aging 19 31751314
2019 GBA1 mutations: Prospects for exosomal biomarkers in α-synuclein pathologies. Molecular genetics and metabolism 19 31761523
2017 Death by over-eating: The Gaucher disease associated gene GBA1, identified in a screen for mediators of autophagic cell death, is necessary for developmental cell death in Drosophila midgut. Cell cycle (Georgetown, Tex.) 19 28933588
2024 Role of GBA variants in Lewy body disease neuropathology. Acta neuropathologica 18 38472443
2022 Exploring the link between GBA1 mutations and Dementia with Lewy bodies, A mini-review. Neuroscience and biobehavioral reviews 18 36084847
2025 Classification and Genotype-Phenotype Relationships of GBA1 Variants: MDSGene Systematic Review. Movement disorders : official journal of the Movement Disorder Society 17 39927608
2024 Cholinergic innervation topography in GBA-associated de novo Parkinson's disease patients. Brain : a journal of neurology 17 37748026
2024 The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1. Science advances 17 38924406
2021 Cognitive Functioning of Glucocerebrosidase (GBA) Non-manifesting Carriers. Frontiers in neurology 17 33716938
2018 Identification of LINC01279 as a cell cycle‑associated long non‑coding RNA in endometriosis with GBA analysis. Molecular medicine reports 17 30106115
2024 African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1. Nature structural & molecular biology 16 39668204
2025 Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids. Brain : a journal of neurology 15 39570889
2023 Association of GBA genotype with motor and cognitive decline in Chinese Parkinson's disease patients. Frontiers in aging neuroscience 15 36845659
2023 Unraveling Autonomic Dysfunction in GBA-Related Parkinson's Disease. Movement disorders clinical practice 15 38026514
2017 Lysosomal defects in ATP13A2 and GBA associated familial Parkinson's disease. Journal of neural transmission (Vienna, Austria : 1996) 15 28894968
2024 Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif. The Journal of biological chemistry 14 38364891
2022 PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases. Proceedings of the National Academy of Sciences of the United States of America 14 36574647
2021 Biochemical markers for severity and risk in GBA and LRRK2 Parkinson's disease. Journal of neurology 14 33388928
2020 The biochemical basis of interactions between Glucocerebrosidase and alpha-synuclein in GBA1 mutation carriers. Journal of neurochemistry 14 31965564
2019 The role of dopamine in the pathogenesis of GBA1-linked Parkinson's disease. Neurobiology of disease 14 31351996
2015 Presenting symptoms of GBA-related Parkinson's disease. Parkinsonism & related disorders 14 25957717
2022 The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models. Disease models & mechanisms 13 35419585
2020 Impulse control behavior in GBA-mutated parkinsonian patients. Journal of the neurological sciences 13 33383316
2024 Molecular mechanisms of the ambroxol action in Gaucher disease and GBA1 mutation-associated Parkinson disease. Neurochemistry international 12 38797393
2024 Variant-specific effects of GBA1 mutations on dopaminergic neuron proteostasis. Journal of neurochemistry 11 38641924
2023 GBA1 in Parkinson's disease: variant detection and pathogenicity scoring matters. BMC genomics 11 37312046
2020 The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects. Orphanet journal of rare diseases 11 33176831
2023 Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis. Movement disorders : official journal of the Movement Disorder Society 10 37921246
2022 Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers. NPJ Parkinson's disease 10 35241697
2022 GBA1 and The Immune System: A Potential Role in Parkinson's Disease? Journal of Parkinson's disease 10 36057834
2021 Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients. Orphanet journal of rare diseases 10 34930372

Missed literature

Know a paper Affinage missed for GBA1? Flag it for the maintainers and the community.

No submissions yet.