Reduced glucocerebrosidase activity in monocytes from patients with Parkinson’s disease

Atashrazm, Farzaneh; Hammond, Deborah; Perera, Gayathri; Dobson‐Stone, Carol; Mueller, Nicole; Pickford, Russell; Kim, Woojin Scott; Kwok, John B.; Lewis, Simon J.G.; Halliday, Glenda M.; Dzamko, Nicolas

doi:10.1038/s41598-018-33921-x

Cited by 93 publications

(102 citation statements)

References 44 publications

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“…[2][3][4][5] We and others have also demonstrated that there is a modest reduction in peripheral glucocerebrosidase enzymatic activity (measured in dried blood spots or monocytes) in sporadic PD compared to controls. 6,7 Carrying GBA variants may affect PD phenotype. PD patients with GBA variants have earlier age of onset and a more rapid motor and cognitive progression than noncarriers with PD.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

Alcalay

Wolf

Chiang

et al. 2020

Ann Clin Transl Neurol

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Objective: Reduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods: We measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genomewide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing. Results: Fifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time. Interpretation: GCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced

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Section: Introductionmentioning

confidence: 99%

Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

Alcalay

Wolf

Chiang

et al. 2020

Ann Clin Transl Neurol

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“…In general, the results concerning GCase levels in different human samples have been inconclusive. GCase protein levels assessed by Western immunoblotting were decreased in monocytes of iPD patients compared to controls [64] and the same was seen in PBMCs derived from PD patients with the A53T mutation in the SNCA gene and different mutations in the GBA gene, although no differences were found in the case of iPD patients [42] . For the case of GBA-PD patients specifically, both an accompanying increase in GBA mRNA levels [42] and a decrease have been reported [65] .…”

Section: Case Of Gcasementioning

confidence: 58%

“…Similarly, in another study in peripheral leukocytes, iPD and PRKN mutation carriers showed no differences in GCase activity compared to controls [74] . However, in a study that specifically assessed monocytes, iPD patients showed reduced GCase activity [64] . GCase activity was also lower in GBA-PD patients and in asymptomatic GBA mutation carriers [64] .…”

Section: Case Of Gcasementioning

confidence: 98%

“…However, in a study that specifically assessed monocytes, iPD patients showed reduced GCase activity [64] . GCase activity was also lower in GBA-PD patients and in asymptomatic GBA mutation carriers [64] . Additionally, no difference in GCase activity was found in fibroblasts derived from iPD patients and healthy controls [48,54] , but decreased activity was found in GBA mutation carriers, including PD patients, asymptomatic carriers and GD patients [48,54] .…”

Section: Case Of Gcasementioning

confidence: 98%

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Autophagy-lysosome pathway as a source of candidate biomarkers for Parkinson’s disease

Papagiannakis¹,

Stefanis²

2020

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Diagnosis of PD relies on clinical history and physical examination, but misdiagnosis is common in early stages. Despite considerable progress in understanding PD pathophysiology, including genetic and biochemical causes, diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease-modifying treatments. Increasing evidence suggests that autophagic dysregulation causes the accumulation of abnormal proteins, such as aberrant α-synuclein, a protein critical to PD pathogenesis. Mutations in the GBA gene are a major PD risk factor and β-glucocerebrosidase (GCase) is also emerging as an important molecule in PD pathogenesis. Consequently, proteins involved in the autophagy-lysosome pathway and GCase protein levels and activity are prime targets for the research and development of new PD biomarkers. The studies so far in PD biological material have yielded some consistent results, particularly regarding the levels of Hsc70, a component of the chaperonemediated autophagy pathway, and the enzymatic activity of GCase in GBA mutation carriers. In the future, larger longitudinal studies, corroborating previous research on possible biomarker candidates, as well as extending the search for possible candidates for other lysosomal components, may yield more definitive results.

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“…Accordingly, studies have identified the fluid biomarker of lysosomal enzymes to measure the central pathological process in PD [7][8][9] . In particular, patients with PD have reduced level of glucocerebrosidase in the blood and cerebrospinal fluid (CSF), which provides a value in diagnosing PD 7,10 .…”

mentioning

confidence: 99%

Changes in plasma arylsulfatase A level as a compensatory biomarker of early Parkinson’s disease

Yoo

Lee

Chung

et al. 2020

Sci Rep

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Lysosomal dysfunction has been associated with Parkinson’s disease (PD). However, the activity of lysosomal enzymes is heterogeneously observed in PD. We investigated whether arylsulfatase A (ARSA) level can be used as a fluid biomarker of PD and can reflect disease progression. Plasma ARSA level was measured in 55 patients with early and drug-naïve PD, 13 patients with late PD, and 14 healthy controls. We compared the plasma ARSA level among the groups and assessed its correlation to clinical parameters and striatal dopamine transporter (DAT) activity. Plasma ARSA level was not correlated with age. The early PD group had higher plasma ARSA level than the control and late PD groups. In a generalized additive model including all patients with PD, the plasma ARSA level showed an inverted U-shape according to disease duration, peaking at 2.19 years. In patients with early PD, plasma ARSA level was positively correlated to parkinsonian motor score and negatively to striatal DAT activity. In summary, plasma ARSA level was elevated in early stage of PD, and elevated plasma ARSA level was correlated to the clinical and imaging markers of nigrostriatal degeneration. These results suggest that ARSA level is a potential biomarker of compensation in early PD.

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Reduced glucocerebrosidase activity in monocytes from patients with Parkinson’s disease

Cited by 93 publications

References 44 publications

Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

Autophagy-lysosome pathway as a source of candidate biomarkers for Parkinson’s disease

Changes in plasma arylsulfatase A level as a compensatory biomarker of early Parkinson’s disease

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