Polymeric nanoparticle-mediated GBA1 gene therapy is neuroprotective in a preclinical model of Parkinson's disease.

Genetic studies have identified the GBA1 gene as a significant genetic risk factor for Parkinson's disease (PD), with 10-15% of PD patients carrying GBA1 variants. GBA1 variants affect the glucocerebrosidase (GCase) enzyme, often leading to reduced GCase activity and associated altered lysosomal function, implicated in PD pathogenesis. Ambroxol, a small molecule widely used for respiratory diseases, has emerged as a potential therapeutic agent for PD, acting by increasing GCase activity. A phase 2 trial demonstrated ambroxol's safety and efficacy in penetrating cerebrospinal fluid (CSF) and engaging with its target in PD patients, including those with GBA1 variants. We present the protocol of the ASPro-PD trial, a phase 3, multicentre, randomised, double-blind, placebo-controlled trial, aimed at evaluating whether high-dose ambroxol improves motor and non-motor function in PD patients. The trial will enrol 330 PD patients with confirmed GBA1 status and the primary outcome will be the combined score of parts I, II, and III of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The secondary outcomes include safety, impact on PD symptoms, and quality of life. Mechanistic and exploratory outcomes include biomarkers related to GCase activity, blood, and CSF biomarkers. This trial is the largest to date to study the effect of ambroxol in PD, utilise a genetically stratified PD population and will provide robust estimates of the efficacy of ambroxol in slowing PD clinical progression.

Lysosomal storage disorders (LSDs) are a diverse group of over 70 rare, inherited metabolic conditions that present significant diagnostic and therapeutic challenges, especially in genetically diverse and resource-limited settings like India. To address the lack of a centralized clinical and genomic data registry for LSDs, we established the first government-supported national LSDs biobank in India. This study describes the infrastructure, sample collection, storage procedures, ethical framework, and expected impact of the biobank on research, diagnostics, and patient care. The study includes biological samples and clinical-genetic data from 530 patients, (526 unrelated individuals and 2 sibling pairs), over a 17-year period (2008-2025). Biological samples including genomic DNA from blood, plasma, and urine precipitate were processed for enzyme and genetic investigations. A centralized webpage has been established to manage the biological sample data including clinical, enzyme and genetic data. The LSD biobank cohort encompasses 8 LSD subgroups across 27 disorders, with the most common being Gaucher disease (n = 70), Tay-Sachs disease (n = 62), Mucolipidosis (ML) II/III (n = 44), and Morquio-A (n = 40). Samples originated from 15 Indian states, with a predominance of pediatric cases. Detailed phenotypic, enzymatic, and genomic profiles were generated. Enzyme assays confirmed markedly reduced activity in most cases, with variable residual activity noted in few LSDs. Genetic analyses using Sanger sequencing, PCR-RFLP, targeted gene panel sequencing, and/ or whole exome sequencing detected causative variants. Notably, c.1469T > C in the IDUA gene (29.4% in Hurler disease), c.230C > G in the GALNS gene (22.5% in Morquio-A disease), c.1448T > C in the GBA1 gene (56% in Gaucher disease), and c.1385C > T and c.964G > T in the HEXA gene (11.3% and 8.1% respectively in Tay-Sachs disease) were the most common variants. Several novel, private mutations were also identified, broadening the mutational landscape of LSDs. The present study represents a scalable model for rare disease research in low- and middle-income countries. This resource lays the foundation for genotype-phenotype correlation studies, natural history analyses, and future precision medicine strategies tailored to the Indian population.

Background: Mutations in the GBA1 gene, leading to glucocerebrosidase (GCase) deficiency, are a major genetic risk factor for Parkinson's disease (PD). While systemic sphingolipid alterations are implicated, their spatial distribution in preclinical stages across central and peripheral tissues remains unclear. Methods: We employed MALDI-MSI to map sphingolipid profiles in the brain, gut, and skin of 12-week-old GBA1 D409V knock-in (KI) mice, an early-stage model of GCase deficiency. Relative lipid intensities were quantified within anatomically defined ROIs. Results: In the brain, homozygous KI mice showed significant accumulation of glucosylceramide (GlcCer) species and GM1 ganglioside specifically within the caudate putamen (CPu) compared to heterozygous mice. Along the gastrointestinal tract, GlcCer (d18:1/18:0) levels progressively increased from the duodenum to the colon, with the most profound accumulation observed in the colonic mucosa of homozygous mice. In the skin, the viable epidermis of homozygous mice exhibited significantly elevated levels of GlcCer (18:1/24:0) and a putative sulfated hexosylceramide. Conclusion: Our findings demonstrate that GCase deficiency induces early, spatially restricted, and tissue-specific sphingolipid alterations across the brain-gut-skin axis prior to overt neurodegeneration. This study establishes a spatially-anchored lipidomic framework, highlighting the colonic mucosa and epidermis as potential sites for accessible biomarker discovery in GBA1-associated parkinsonism.

Parkinson's disease (PD) is the second most common neurodegenerative disease and the fastest-growing disability-causing neurological disorder worldwide. Based on the CPDR cohort from 19 clinical centers, we summarized the mortality information and characteristics of patients with PD, and analyzed the related factors affecting their survival. After a 6-year follow-up period, 562 of the 3,148 patients died, with a mortality rate of 3.03 deaths per 100 person-years, and a median survival time from disease onset of 23.33years. The most common cause of death was cardiovascular disease, followed by cerebrovascular disease and respiratory disease. Older age at onset, carriers of GBA1 gene variants, type 2 diabetes, higher LEDD, late H&Y stage (especially H&Y stage 4 and H&Y stage 5), higher UPDRS part Ⅲ scores, a history of falls, depression, and cognitive dysfunction were associated with increased mortality. In contrast, undergoing deep brain stimulation (DBS) surgery and higher educational attainment was associated with a lower risk of death. Our findings contributed to further expanding the survival data of PD and advocated for early identification of high-risk patients for timely intervention to improve prognosis.

Background: Variants in the GBA gene represent the most common genetic risk factor for Parkinson's disease and are associated with a more aggressive disease course. Deep brain stimulation is an established therapy for advanced Parkinson's disease, yet the influence of GBA status on postoperative outcomes remains incompletely defined. This review aims to summarize the clinical relevance of GBA genotyping prior to DBS and to evaluate its potential contribution to decision-making, risk stratification, and long-term management. Methods: A structured narrative review was conducted. The literature on sequencing methodology, variant interpretation, and postoperative outcomes in GBA-positive and GBA-negative patients was examined. Particular focus was placed on motor, cognitive, and neuropsychiatric outcomes, and on studies comparing trajectories across variant classes. Results: Across all study designs, patients with GBA-associated Parkinson's disease demonstrated robust motor improvement after DBS, with outcomes comparable to those in non-carriers. Cognitive and neuropsychiatric decline occurred more rapidly in GBA carriers. Recent evidence indicates that cognitive and neuropsychiatric decline is influenced more by the genetic profile than the stimulation procedure. Variant severity appears to influence postoperative trajectories. Long-read sequencing improves detection of recombinant alleles and may refine genotype-phenotype associations. Genotyping provides additional value in counseling, expectation management, and postoperative planning. Conclusions: DBS remains an effective motor therapy for patients with GBA-associated Parkinson's disease. Current findings indicate GBA genotyping should inform, and not limit, candidate selection. Integration of clinical, cognitive and genetic data supports more individualized management. Methodological advances in sequencing and the development of prediction models may further enhance personalized DBS planning.

Addition of Lyso-Gb1 to enzyme activity to first-tier test for Gaucher in DBS improves diagnostic accuracy and reduces patient recall rate.

Parkinson's disease (PD) is a neurodegenerative disorder with a complex interaction between genetic and environmental causal factors. The role of Lewy body (LB) pathology (Lewy bodies and neurites) in genetic PD remains unclear, as some gene mutations do not consistently present with alpha-synuclein aggregates or LB in postmortem studies. This review aims to evaluate neuropathological data from genetic PD cases, focusing on the prevalence of LB pathology and co-pathologies, as well as the relationship between neuropathological findings and relevant clinical features. Case reports, case series, and clinicopathological cohorts published between 1990 and 2024 were reviewed. Clinical information and data on LB pathology, tau pathology, amyloid-β deposition, and TDP-43 pathology were extracted. Among 243 genetic PD cases with autopsy data, LB pathology was present in 79% and varied by gene mutation. All SNCA and most GBA gene mutation cases (98%) exhibited LB pathology, while it was observed in 59% of LRRK2 cases and only 32% of PARKIN-related PD. LB pathology was associated with a later disease onset (54.6 vs. 44.7years, p < 0.001), shorter disease duration (14.8 vs. 27.7years, p < 0.001) and cognitive impairment (OR: 15.9, p < 0.001). Co-pathologies did not differ among gene mutations. LB pathology is not universally present in genetic PD, particularly in LRRK2 and PARKIN mutations, highlighting challenges for the development of synuclein-based biomarkers and the need for genetic considerations in clinical trials targeting alpha-synuclein.

The human GBA1 gene encodes glucocerebrosidase (GCase), a lysosomal enzyme that hydrolyzes glucosylceramides. Variants in GBA1 and reduced GCase activity have been linked to Parkinson's disease and Gaucher's disease. Here we have characterized twenty-four GCase commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While the use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Parkinson's disease (PD) involves α-synuclein (αSyn) oligomerization and aggregation, processes facilitated by glycosphingolipids. Defective glycosphingolipid transport and degradation-especially via the lipid-degrading enzyme glucocerebrosidase 1 (GCase, gene GBA1)-aggravate PD and increase dementia risk. Ambroxol is a mucolytic drug and has emerged as a promising add-on therapy for PD since it acts as a chaperone for misfolded GCase, thereby increases the likelihood that mutated and misfolded GCase eludes ER-associated degradation (ERAD) and is transported to its destination, the lysosome. In this study we investigated whether and how ambroxol provided therapeutic benefits for PD irrespective of the GBA1 mutation status. Pink1-/-/SNCAA53T double mutant PD mice were administered ambroxol either via the drinking water (120-150 mg·kg-1·d-1) or via food pellets (75-100 mg·kg-1·d-1) for approximately 6 months. During the treatments mice were observed in IntelliCages; and in motor, sensory and cognitive functions tests. After mice were euthanized, tissues were dissected for protein, lipidomic and metabolomic analyses. We showed that high-dose long-term ambroxol was well tolerated and led to mild behavioral and metabolic improvements but had adverse effects on brain sulfatides, lysosomal functions and mitochondrial cardiolipins. Notably, brain levels of glucosylceramides (GlcCer 16:0) were normalized, while sulfatides (SHexCer) further increased. Western blots revealed a modest reduction of αSyn and phosphorylated αSyn (P-Ser129). IntelliCage assessments showed increased exploratory activity with ambroxol, suggesting reduced bradykinesia, though sensory and motor functions remained unchanged. Lipidomic profiles of mitochondria showed accumulation of HexCer and triglycerides in PD mitochondria, regardless of treatment, while ambroxol led to an additional decline of cardiolipins including the most abundant tetralinoleoyl cardiolipins. In HT22 hippocampal neurons preloaded with αSyn pre-formed fibrils, ambroxol accumulated within lysosomes, increased lysosomal mass and sphingolipid content and promoted lysosomal enzyme release. Collectively, these results suggest that ambroxol confers transient behavioral benefits and modestly reduces αSyn pathology, albeit with potential drawbacks. In addition, its lysosomal accumulation may further disrupt sphingolipid metabolism and impair mitochondrial compensatory mechanisms. Ambroxol-induced lysosomal exocytosis may transiently relieve αSyn burden, but further interventions would be required to ensure αSyn clearance from the brain.

BackgroundNearly half of Parkinson's disease (PD) patients are diagnosed with dementia within 10 years of their initial diagnosis. It is likely that these subgroups of patients experience symptoms of cognitive decline before the diagnosis of PD. Therefore, it is important to study trajectories of age‐related cognitive decline in individuals at risk of PD.MethodThe National Institute for Health and Care Research's Genes and Cognition (G&C) study has conducted cognitive profiling across several domains (11 cognitive tests) in approximately 35,000 individuals. Nearly one‐third of these participants completed a second cognitive assessment approximately 41 months after the first. Participants provided basic demographic information at the time of recruitment to the NIHR Bioresource. Currently, genetic information for 9,878 participants is available, with the remaining participants undergoing genotyping. We will use the polygenic risk score (PRS) catalog number PGS004924 (90 genetic variants) to calculate the PRS for PD in G&C study participants. Individuals in the top 2.5th percentile will be categorized as high‐risk, while the rest will be categorized as low risk for PD. Additionally, known common variants in GBA, LRRK2, MAPT and SNCA gene will be investigated.ResultBased on the available data, demographic and clinical characteristics will be compared between individuals with high and low polygenic risk for PD using parametric and/or non‐parametric tests. Cognitive test performance across the 11 tests will be compared between the high‐ and low‐polygenic‐risk groups for PD at both time points. Additionally, cognitive test performance will be investigated for common risk variants of PD.ConclusionThis study will provide insights into the trajectories of performance across various cognitive domains in individuals at high risk for PD. Identifying the cognitive domains most sensitive to decline in PD will support efforts for early detection and management.

Background/Objectives: Pathogenic variants in the GBA1 gene, which encodes the lysosomal enzyme -glucocerebrosidase, cause Gaucher disease (GD) and represent one of the strongest genetic risk factors for Parkinson’s disease (PD). However, not all carriers develop PD, suggesting the involvement of additional modifiers. Transcriptomic alterations shared between GD and PD may reveal such modifiers and provide insights into the mechanisms linking GBA1 to PD. Methods: Eighteen transcriptomic datasets spanning GD, GBA1-associated PD, and sporadic PD were integrated to identify shared, directionally concordant differentially expressed genes, followed by pathway enrichment analysis. Causal relationships were assessed using two-sample Mendelian randomisation with whole-blood and brain genetic instruments and PD GWAS summary statistics. Diagnostic relevance was evaluated in independent datasets using machine learning, while metabolic implications were explored with a neuron-specific genome-scale metabolic model. Results: Shared DEGs were enriched in lysosomal, lipid, redox, and endocrine pathways. Mendelian randomisation prioritised 12 risk genes in whole blood and 5 in brain tissue, with 4 overlapping; risk-increasing effects were observed for GPNMB, MMP9, TRIM22, TESMIN, NFE2L3, FAM89A, METTL7A, PID1, NECAB2, and LPL, whereas GIPR and RASGRF2 showed protective effects, and AGT was brain-specific. Diagnostic signals were concentrated in a subset of genes, while metabolic modelling revealed convergent but subtype-specific perturbations across metabolic circuits. Conclusions: Convergent genetic, transcriptomic, and metabolic evidence supports at least two mechanistic routes to PD risk: a GBA1-sensitised lysosomal–lipid/redox axis, and a GBA1-independent neuronal–endocrine axis. These findings explain the variable risk among GBA1 carriers, identify candidate biomarkers, and highlight pathway-anchored targets for stratified intervention.

Variants in the GBA1 gene can increase the risk of Parkinson's disease (PD) by reducing glucocerebrosidase (GCase) activity, disrupting lysosomal and mitochondrial function, and increasing alpha-synuclein aggregation. The molecule GT-02287 prevents misfolding of GCase and ameliorates downstream pathway abnormalities. To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GT-02287. The safety, tolerability, and plasma pharmacokinetics of single and multiple oral doses were evaluated in 73 healthy volunteers, and GT-02287 levels in cerebrospinal fluid (CSF) and GCase activity in blood were measured. All dose levels tested were safe and generally well-tolerated. No serious or severe adverse events occurred. The most common events were nausea and headache. Plasma and CSF exposures were within the projected therapeutic range, and GCase activity increased after GT-02287 administration. GT-02287 was safe and well-tolerated in healthy volunteers. Plasma and CSF levels were consistent with levels in rodents that modulate PD biology. © 2025 International Parkinson and Movement Disorder Society.

When growth hormone deficiency isn't the answer: A case of gaucher disease

Trial in progress: Galileo-3, a Phase 3 safety and efficacy trial of FLT201 gene therapy in patients with gaucher disease type 1

BackgroundGaucher disease (GD) is a lysosomal disease caused by mutations in the GBA1 gene, leading to glucosylceramide and glucosylsphingosine accumulation. GBA1 mutations are also the most common genetic risk factor for Parkinson’s disease (PD). Increased expression of glycoprotein non-metastatic melanoma protein B (gpNMB), a potential biomarker of inflammation and neurodegeneration, has been reported in PD, GD and other LSDs. Plasma concentrations of gpNMB are correlated with the accumulation of bioactive lipid substrates in several chronic inflammatory diseases and gpNMB stimulates lipogenesis in white adipocytes. To explore its potential significance in GD we measured plasma gpNMB in patients with Gaucher Disease type 1 (GD1), Gaucher Disease Type 3 (GD3), GD1-PD, PD and GBA heterozygous PD and in different clinicopathological subtypes.ResultsThe study enrolled participants the GAUCHERITE Cohort in the UK (172 GD1 and 20 GD3 patients) and the Biopark Cohort (72 IPD patients) in Sweden. Plasma concentrations of gpNMB were significantly higher in patients with Gaucher disease (mean: 200.9; range: 9.8-1643 ng/ml) compared with healthy controls (mean: 35.1; range.: 10.1- 125 ng/ml), including those receiving enzyme replacement therapy (ERT). Notably, gpNMB concentrations remained elevated in GD1 patients who had received ERT for more than 5 years. The biomarker was particularly elevated in patients who had been splenectomized, those with known pulmonary or liver disease, and those with monoclonal gammopathy, despite enzyme therapy. No statistical difference was found in plasma gpNMB concentrations between treated patients with GD1 and GD3. On average, there was no difference in plasma gpNMB concentrations between Gaucher patients with or without Pakinsonism. As expected however plasma gpNMB concentrations among patients with Parkinsonism were higher in those with type 1 Gaucher disease than either GBA1 heterozygotes or those with idiopathic PD (p=0.0001).ConclusionOur findings indicate that the association of plasma gpNMB with liver cirrhosis, gammopathy and pulmonary disease in Gaucher disease warrants further investigation. Additionally, plasma gpNMB may serve as a supportive biomarker in the evaluation and clinical monitoring of residual disease activity. However, plasma gpNMB neither differentiated between the neuronopathic subtypes of Gaucher disease nor idiopathic Parkinson’s disease.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13023-025-04054-y.

Background/Objectives: Gaucher disease type 1 is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the GBA1 gene. Although enzyme replacement therapy has improved patient outcomes, there is limited long-term real-world data on taliglucerase alfa. This study aimed to evaluate the long-term efficacy and safety of taliglucerase alfa in both treatment-naïve and previously treated patients with Gaucher disease type 1 over a 10-year period. Methods: This prospective, single-centre cohort study involved 29 patients (13 treatment-naïve and 16 previously treated with imiglucerase) who received taliglucerase alfa from 2015 to 2024. Clinical, hematological, visceral, skeletal, and biochemical parameters were assessed at baseline and at 12, 60, and 120 months. Biomarkers included chitotriosidase and glucosylsphingosine. Safety was evaluated through adverse event reporting and anti-drug antibody testing. Results: Hemoglobin and platelet counts improved or remained stable in all patients. By 60 months, liver volume had normalised in treatment-naïve patients (mean reduction: 23.1%), while spleen volume had decreased by up to 47.3%. Lyso-Gb1 levels decreased by 86.1% in patients who had not previously received treatment and by 59.5% overall, with a strong correlation to adherence. Bone mineral density improved in most cases. 137 adverse events were reported, 24% of which were mild infusion-related reactions. Anti-drug antibody developed in two patients, including one with a reduced therapeutic response. Conclusions: Taliglucerase alfa offers sustained long-term clinical, hematological and biochemical benefits in both treatment-naïve and previously treated Gaucher disease type 1 patients, with a favorable safety profile. Glucosylsphingosine proved to be a highly sensitive biomarker for monitoring therapeutic efficacy and detecting treatment response.

A pathogenic alpha synuclein variant exacerbates disease progression in a neuron-specific Gba-KO mouse.

Genetic analysis of GBA1 gene in a cohort of patients with Parkinson's disease.

Variants in the GBA1 gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype-phenotype correlations exist but with conflicting data. Here, we compared the clinical phenotype of 183 idiopathic PD (iPD) patients, 39 severe GBA1-PD, 24 mild GBA1-PD, and 55 risk GBA1-PD. Compared to iPD, we observed that only severe GBA1-PD patients had a distinctive, more several clinical profile, characterised by worse depression, hyposmia, cognitive dysfunction, and possibly constipation.