Human Peripheral Blood Macrophages As a Model for Studying Glucocerebrosidase Dysfunction

Николаев, Михаил; Kopytova, Alena E.; Байдакова, Г. В.; Anton, Emil; Salogub, Galina; Senkevich, Konstantin; Usenko, Tatiana; Горчакова, М. В.; Kovalchuk, Yu.; Беркович, О. А.; Zakharova, Ekaterina; Pchelina, Sofya

doi:10.1134/s1990519x19020081

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…PBMCs were differentiated by the macrophage colony-stimulating factor (M-CSF) (10 ng/ml) (Sigma-Aldrich, Burlington, MA, USA) in RPMI 1640 medium (Gibco, Waltham, MA, USA) supplemented with 10% FCS (Gibco, Waltham, MA, USA) with harvesting after 5 days. Phenotypical maturation of monocyte-derived macrophages was confirmed by light microscopy and flow cytometry with specific antibodies to CD14+ and CD68+ (eBioscience, San Diego, CA, USA), as described earlier [18,21].…”

Section: Differentiation Of Human Monocytes To Macrophagesmentioning

confidence: 99%

Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease

Usenko

Bezrukova

Basharova

et al. 2021

Genes

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Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson’s disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. PD carriers of severe mutation L444P in the GBA gene is characterized by the earlier age at onset compared to N370S. Not every carrier of GBA mutations develop PD during one’s lifetime. In the current study we aimed to find common gene expression signatures in PD associated with mutation in the GBA gene (GBA-PD) using RNA-seq. We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.

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Section: Differentiation Of Human Monocytes To Macrophagesmentioning

confidence: 99%

Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease

Usenko

Bezrukova

Basharova

et al. 2021

Genes

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“…Для дальнейшей дифференцировки в макрофаги культивировали клетки в среде RPMI 1640 (Gibco, USA), содержащей: 10% FBS (Gibco, USA), 1% гентамицин (Gibco, USA), 10 нг/мл колониестимулирующий фактор макрофагов (М-КСФ) (Sigma-Aldrich, USA). На 4-ый день культивирования добавля-ли ФШ: ABX (Sigma-Aldrich, USA) -50 мкмоль, аллостерический ФШ NCGC00241607, как описано ранее [3] и два соединения, являющиеся химическими модификациями данного ФШ − 4 мкмоль. Ферментативную активность GCase и концентрацию HexSph оценивали методом тандемного масс-спектрометрического анализа [3].…”

Section: материалы и методыunclassified

“…На 4-ый день культивирования добавля-ли ФШ: ABX (Sigma-Aldrich, USA) -50 мкмоль, аллостерический ФШ NCGC00241607, как описано ранее [3] и два соединения, являющиеся химическими модификациями данного ФШ − 4 мкмоль. Ферментативную активность GCase и концентрацию HexSph оценивали методом тандемного масс-спектрометрического анализа [3]. Транслокацию GCase (Alexa Fluor 488) в лизосомы (маркер LAMP2 (Cy3)) оценивали в макрофагах пациентов с использованием лазерного конфокального микроскопа Leica TCS-SP5 (объектив х63) (Leica, Germany).…”

Section: материалы и методыunclassified

Pharmacological chaperones glucocerebrosidase as treatment of Gaucher disease

Kopytova¹,

Николаев²,

Богданова³

et al. 2020

Nauchno-Prakticheskii Zhurnal «Medicinskaia Genetika»

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Мутации в гене лизосомного фермента глюкоцереброзидазы (GBA), приводящие к дисфункции фермента глюкоцереброзидазы (GCase), в гомозиготном состоянии вызывают болезнь Гоше (БГ), а в гетерозиготном состоянии повышают риск развития болезни Паркинсона (БП). Обсуждается использование фармакологических шаперонов (ФШ) GСase для терапии как БГ, так и GBA-ассоциированной БП (GBA-БП). Используя ФШ амброксол мы показали увеличение ферментативной активности GCase и снижение концентрации лизосфинголипидов HexSph в культуре первичных макрофагов пациентов с БГ и GBA-БП. Впервые проведена оценка эффективности новых химических соединений, модификаций ранее описанного аллостерического ФШ. Gaucher disease (GD), caused by GBA mutations, encodes lysosomal enzyme glucocerebrosidase (GCase). Pharmacological chaperones could potentially enhance GCase activity and treat GD and PD linked to mutations in the GBA gene (GBA-PD). Using ABX as pharmacological chaperone for macrophages derived from GD and GBA-PD patients we observed significantly enhanced GCase activity and decrease of HexSph concentration. For the first time was evaluated the effectiveness of chemical modifications of the previously described allosteric pharmacological chaperone.

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Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy

et al. 2022

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Human Peripheral Blood Macrophages As a Model for Studying Glucocerebrosidase Dysfunction

Cited by 7 publications

References 21 publications

Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease

Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease

Pharmacological chaperones glucocerebrosidase as treatment of Gaucher disease

Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy

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