Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and dementia with Lewy bodies

BackgroundLysosomal dysfunction is thought to be a prominent feature in the pathogenetic events leading to Parkinson’s disease (PD). This view is supported by the evidence that mutations in GBA gene, coding the lysosomal hydrolase β-glucocerebrosidase (GCase), are a common genetic risk factor for PD. Recently, GCase activity has been shown to be decreased in substantia nigra and in cerebrospinal fluid of patients diagnosed with PD or dementia with Lewy Bodies (DLB). Here we measured the activity of GCase and other endo-lysosomal enzymes in different brain regions (frontal cortex, caudate, hippocampus, substantia nigra, cerebellum) from PD (n = 26), DLB (n = 16) and age-matched control (n = 13) subjects, screened for GBA mutations. The relative changes in GCase gene expression in substantia nigra were also quantified by real-time PCR. The role of potential confounders (age, sex and post-mortem delay) was also determined.FindingsSubstantia nigra showed a high activity level for almost all the lysosomal enzymes assessed. GCase activity was significantly decreased in the caudate (−23%) and substantia nigra (−12%) of the PD group; the same trend was observed in DLB. In both groups, a decrease in GCase mRNA was documented in substantia nigra. No other lysosomal hydrolase defects were determined.ConclusionThe high level of lysosomal enzymes activity observed in substantia nigra, together with the selective reduction of GCase in PD and DLB patients, further support the link between lysosomal dysfunction and PD pathogenesis, favoring the possible role of GCase as biomarker of synucleinopathy. Mapping the lysosomal enzyme activities across different brain areas can further contribute to the understanding of the role of lysosomal derangement in PD and other synucleinopathies.

• Publication year

  2015

• Venue

  Molecular Neurodegeneration

• Publication date

  2015-03-27

• Fields of study

  Medicine, Psychology

• Identifiers
  DOI 10.1186/s13024-015-0010-2PMID 25881142PMCID 4428238
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• R: A language and environment for statistical computing.

  2014cited by this paper
• Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells

  2014cited by this paper
• Neuroinflammation and α-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction.

  2014cited by this paper
• Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson's disease.

  2014influential reference
• Factors Influencing the Measurement of Lysosomal Enzymes Activity in Human Cerebrospinal Fluid

  2014influential reference
• Cerebrospinal Fluid Lysosomal Enzymes and Alpha-Synuclein in Parkinson's Disease

  2014cited by this paper
• The genetics of Parkinson's disease: Progress and therapeutic implications

  2013cited by this paper
• Changes in endolysosomal enzyme activities in cerebrospinal fluid of patients with Parkinson's disease

  2013cited by this paper
• A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies.

  2013cited by this paper
• Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage

  2013cited by this paper
• Relationship between mitochondria and α-synuclein: a study of single substantia nigra neurons.

  2012cited by this paper
• Glucocerebrosidase Deficiency in Substantia Nigra of Parkinson Disease Brains

  2012cited by this paper
• Glucocerebrosidase Mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease

  2012cited by this paper
• Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.

  2011cited by this paper
• Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

  2011cited by this paper
• The relationship between mitochondria and α-synuclein-A study of single substantia nigra neurons

  2011cited by this paper
• Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

  2009cited by this paper
• Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in Dementia with Lewy Bodies.

  2009cited by this paper
• Analyzing real-time PCR data by the comparative CT method

  2008cited by this paper
• The chemical neurobiology of carbohydrates.

  2008cited by this paper
• The pathogenesis of cell death in Parkinson's disease – 2007

  2007cited by this paper
• Lysosomal hydrolases in cerebrospinal fluid from subjects with Parkinson's disease

  2007cited by this paper
• The pathogenesis of cell death in Parkinson's disease

  2006cited by this paper
• Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization

  2006cited by this paper
• Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews.

  2004cited by this paper
• Glucocerebrosidase mutations in subjects with parkinsonism.

  2004cited by this paper

• Pathological Protein Targets in Parkinson's Disease: Progress Towards the Development of Disease-Modifying Therapies.

  2026cites this paper
• GBA genotype-Parkinson’s phenotype correlation in a cohort of 252 Italian patients from the Tuscany region

  2025cites this paper
• Relationship of cognitive decline with glucocerebrosidase activity and amyloid‐beta 42 in DLB and PD

  2025cites this paper
• Precision Medicine in Parkinson's Disease.

  2025cites this paper
• Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain

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• Neurodegeneration and aging: pathophysiology, diagnosis, and therapeutic targets

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  2025cites this paper
• Modest improvement of metabolic and behavioral deficits with long-term ambroxol treatment in a Pink1-/-SNCAA53T double mutant mouse model of Parkinson's disease.

  2025cites this paper
• LRRK2 kinase activity regulates Parkinson’s disease-relevant lipids at the lysosome

  2025cites this paper
• A pathogenic alpha synuclein variant exacerbates disease progression in a neuron-specific Gba-KO mouse.

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• Inhibition of cysteine protease cathepsin Lincreases the level and activity of lysosomal glucocerebrosidase

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  2023cites this paper
• Lewy Body Dementia: An Overview of Promising Therapeutics

  2023cites this paper
• Emerging drugs for dementia with Lewy Bodies: a review of Phase II & III trials

  2023cites this paper
• GBA1 Variants and Parkinson’s Disease: Paving the Way for Targeted Therapy

  2023cites this paper
• Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

  2023cites this paper
• LRRK2 and GBA1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts

  2023cites this paper
• Role of novel endpoints and evaluations of response in Parkinson disease.

  2023cites this paper
• Role of rodent models in advancing precision medicine for Parkinson's disease.

  2023cites this paper
• Genetic mechanism vs genetic subtypes: The example of GBA.

  2023cites this paper
• Biomarkers of diagnosis, prognosis, pathogenesis, response to therapy: Convergence or divergence? Lessons from Alzheimer's disease and synucleinopathies.

  2023cites this paper
• The definition of precision medicine in neurodegenerative disorders and the one disease-many diseases tension.

  2023cites this paper
• Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease.

  2022cites this paper
• Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease

  2022cites this paper
• GBA Mutation Analysis in Turkish Parkinson’s Disease Patients: Comparison of Clinical and Cognitive Performance

  2022cites this paper
• Clinical Sphingolipids Pathway in Parkinson’s Disease: From GCase to Integrated-Biomarker Discovery

  2022cites this paper
• GBA Variants and Parkinson Disease: Mechanisms and Treatments

  2022cites this paper
• Lysosomal ceramides regulate Cathepsin B-mediated processing of saposin C and glucocerebrosidase activity.

  2022cites this paper
• Glucocerebrosidase-associated Parkinson disease: Pathogenic mechanisms and potential drug treatments.

  2022cites this paper
• LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease

  2022cites this paper
• LRRK2 Kinase Activity Regulates Parkinson’s Disease-Relevant Lipids at the Lysosome

  2022cites this paper
• Altered expression of glycobiology-related genes in Parkinson’s disease brain

  2022cites this paper
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  2022cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
• Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders

  2021cites this paper
• Glucocerebrosidase mutations: A paradigm for neurodegeneration pathways.

  2021cites this paper
• Parkinson’s Disease Associated with GBA Gene Mutations: Molecular Aspects and Potential Treatment Approaches

  2021cites this paper
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  2021cites this paper
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  2021cites this paper
• Constitutive silencing of LRRK2 kinase activity leads to early glucocerebrosidase deregulation and late impairment of autophagy in vivo.

  2021cites this paper
• Genetic Architecture and Molecular, Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art, Opportunities and Challenges

  2021cites this paper
• Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

  2020cites this paper
• The impact of proteostasis dysfunction secondary to environmental and genetic causes on neurodegenerative diseases progression and potential therapeutic intervention

  2020cites this paper
• Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

  2020cites this paper
• Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

  2020cites this paper
• Molecular profiling in Parkinsonian syndromes: CSF biomarkers.

  2020cites this paper
• Systematic review of gene expression studies in people with Lewy body dementia

  2020cites this paper
• Lipids in Neurodegenerative Diseases

  2020cites this paper
• Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

  2020cites this paper
• Common Variants Coregulate Expression of GBA and Modifier Genes to Delay Parkinson's Disease Onset

  2020cites this paper
• High Glucosylceramides and Low Anandamide Contribute to Sensory Loss and Pain in Parkinson's Disease

  2020cites this paper
• Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson’s Disease

  2020cites this paper
• Region-specific characterization of N-glycans in striatum and substantia nigra of an adult rodent brain.

  2020cites this paper
• Glycosphingolipids and neuroinflammation in Parkinson’s disease

  2020cites this paper
• Lysosomal enzyme deficiency and GBA mutations in Dystonia

  2020influential citation
• The Emerging Role of the Lysosome in Parkinson’s Disease

  2020cites this paper
• Novel β-Glucocerebrosidase activators that bind to a new pocket at a dimer interface and induce dimerization.

  2020cites this paper
• When lipid homeostasis runs havoc: lipotoxicity links lysosomal dysfunction to autophagy.

  2020cites this paper
• The interplay between Glucocerebrosidase, α-synuclein and lipids in human models of Parkinson's disease.

  2020cites this paper
• Recent advances and perspectives of metabolomics-based investigations in Parkinson’s disease

  2019cites this paper
• Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery

  2019cites this paper
• Dysfunction of Cellular Proteostasis in Parkinson’s Disease

  2019cites this paper
• GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

  2019cites this paper
• Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult.

  2019cites this paper
• Autophagic- and Lysosomal-Related Biomarkers for Parkinson’s Disease: Lights and Shadows

  2019cites this paper
• Lysosomal enzyme activities as possible CSF biomarkers of synucleinopathies.

  2019cites this paper
• The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

  2019cites this paper
• Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

  2019cites this paper
• The effect of mutant GBA1 on accumulation and aggregation of α-synuclein.

  2019cites this paper
• Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations

  2019cites this paper
• Path mediation analysis reveals GBA impacts Lewy body disease status by increasing α-synuclein levels.

  2019cites this paper
• A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease

  2019cites this paper
• LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease

  2019cites this paper
• Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer’s and Parkinson’s disease

  2019cites this paper
• The role of dopamine in the pathogenesis of GBA1-linked Parkinson's disease.

  2019cites this paper
• Trends in Glycolipid Biomarker Discovery in Neurodegenerative Disorders by Mass Spectrometry.

  2019cites this paper
• Alteration of Sphingolipids in Biofluids: Implications for Neurodegenerative Diseases

  2019cites this paper
• Age-related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia.

  2019cites this paper