Parkinson's Disease: <i>Glucocerebrosidase 1</i> Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

Lerche, Stefanie; Wurster, Isabel; Röeben, Benjamin; Zimmermann, Milan; Riebenbauer, Benjamin; Deuschle, Christian; Hauser, Ann‐Kathrin; Schulte, Claudia; Berg, Daniela; Maetzler, Walter; Waniek, Katharina; Lachmann, Ingolf; Liepelt‐Scarfone, Inga; Gasser, Thomas; Brockmann, Kathrin

doi:10.1002/mds.27884

Cited by 39 publications

(44 citation statements)

References 19 publications

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“…To date, only a few studies have attempted to delineate the phenotypic profile associated to specific mutation classes, showing earlier age at onset and a greater risk for dementia and other nonmotor symptoms in carriers of severe variants. 10,[18][19][20][21] In the present study, we further addressed this issue by dividing patients with GBA-PD into subgroups based on the variant type and attempted to profile the clinical features that recurred more frequently, or earlier in the disease course, within each subgroup. Severe GBA variants were characterized by younger onset and more severe progression as per the shorter time to develop balance disturbances and the higher risk of hallucinations and cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

GBA‐Related Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

et al. 2020

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Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. Objectives: We determined the frequency of GBArelated PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. Methods: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. β-glucocerebrosidase activity was measured. The Kaplan-Meier method and Cox proportional hazard regression models were performed. Results: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA-PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA-PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA-PD had the lowest β-glucocerebrosidase activity. Conclusions: GBA-PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles.

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Section: Discussionmentioning

confidence: 99%

GBA‐Related Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

et al. 2020

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“…Recently, Lerche et al (2020) showed reduced CSF levels of total alpha-synuclein in GBA-PD compared to iPD and controls. Moreover, in this study, GBA-PD subjects bearing a severe mutation showed lower CSF levels of total alpha-synuclein than GBA-PD with mild or risk variant mutations or iPD patients.…”

Section: Biochemical Markersmentioning

confidence: 99%

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Avenali

Blandini

Cerri³

2020

Front. Aging Neurosci.

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Heterozygous mutations of the GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), occur in a considerable percentage of all patients with sporadic Parkinson's disease (PD), varying between 8% and 12% across the world. Genome wide association studies have confirmed the strong correlation between PD and GBA1 mutations, pointing to this element as a major risk factor for PD, possibly the most important one after age. The pathobiological mechanisms underlying the link between a defective function of GCase and the development of PD are still unknown and are currently the focus of intense investigation in the community of pre-clinical and clinical researchers in the PD field. A major controversy regards the fact that, despite the unequivocal correlation between the presence of GBA1 mutations and the risk of developing PD, only a minority of asymptomatic carriers with GBA1 mutations convert to PD in their lifetime. GBA1 mutations reduce the enzymatic function of GCase, impairing lysosomal efficiency and the cellular ability to dispose of pathological alpha-synuclein. Changes in the cellular lipidic content resulting from the accumulation of glycosphingolipids, triggered by lysosomal dysfunction, may contribute to the pathological modification of alpha-synuclein, due to its ability to interact with cell membrane lipids. Mutant GCase can impair mitochondrial function and cause endoplasmic reticulum stress, thereby impacting on cellular energy production and proteostasis. Importantly, reduced GCase activity is associated with clear activation of microglia, a major mediator of neuroinflammatory response within the brain parenchyma, which points to neuroinflammation as a major consequence of GCase dysfunction. In this present review article, we summarize the current knowledge on the role of GBA1 mutations in PD development and their phenotypic correlations. We also discuss the potential role of the GCase pathway in the search for PD biomarkers that may enable the development of disease modifying therapies. Answering these questions will aid clinicians in offering more appropriate counseling to the patients and their caregivers and provide future directions for PD preclinical research.

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“…Indeed, we could show that PD GBA present with lower CSF levels of total alpha-synuclein compared to healthy controls and also compared to PD GBA_wild type . Importantly, PD GBA with severe variants show the lowest mean values ( Lerche et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

Brockmann

2020

Front. Cell Dev. Biol.

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Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

Cited by 39 publications

References 19 publications

GBA‐Related Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

GBA‐Related Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

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