Could Blood Hexosylsphingosine Be a Marker for Parkinson's Disease Linked with <scp><i>GBA1</i></scp> Mutations?

Kopytova, Alena E.; Usenko, Tatiana; Baydakova, Galina; Николаев, Михаил; Senkevich, Konstantin; Izyumchenko, Artem D.; Tyurin, Alexandr; Miliukhina, Irina; Anton, Emil; Zakharova, Ekaterina; Пчелина, С. Н.

doi:10.1002/mds.29132

Cited by 9 publications

(4 citation statements)

References 6 publications

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“…The development mechanism of GBA-PD remains unknown. A decrease in GCase activity and accumulation of lysosphingolipids in patients with GBA-PD was shown by us and other researchers [1,2]. GCase dysfunction is thought to result in impaired autophagy and accumulation of the alpha-synuclein protein, which is a crucial process in neurodegeneration in PD.…”

mentioning

confidence: 71%

“…Механизм развития GBA-БП остаётся неизвестными. Нами и другими авторами было показано снижение активности GCase и накопление лизосфинголипидов у пациентов с GBA-БП как в периферической крови, так и клетках мозга [1,2]. Предполагается, что дисфункция GCase может приводить к нарушению аутофагии и накоплению белка альфа-синуклеина, олигомеризация которого является ключевым процессом нейродегенерации при БП.…”

Section: аннотацияunclassified

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Genomic studies of neudegeneration in Parkinson’s disease associated with glucocerebrosodase dysfunction on cell and animals models

Pchelina,

Bezrukova,

Rudenok

et al. 2023

Genes & Cells

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Mutations in the glucocerebrosidase gene (GBA1), which encodes the lysosomal enzyme glucocerebrosidase (GCase), can cause Gaucher disease, an autosomal recessive disease, and increase the risk of Parkinson’s disease (PD). The risk of developing PD for carriers of homozygous and heterozygous GBA1 mutations increases by 8–10 times, but not all carriers develop PD during their lifetime. Additionally, GBA-associated PD (GBA-PD) represents 10 to 30% of all forms of parkinsonism. The development mechanism of GBA-PD remains unknown. A decrease in GCase activity and accumulation of lysosphingolipids in patients with GBA-PD was shown by us and other researchers [1, 2]. GCase dysfunction is thought to result in impaired autophagy and accumulation of the alpha-synuclein protein, which is a crucial process in neurodegeneration in PD. Several techniques based on modeling parkinsonism in mice with GCase dysfunction were used to study the impact of GCase dysfunction on DA neuron neurodegeneration [3, 4]. In this study, we evaluated GCase activity, lysosphingolipids level, and the degree of neurodegeneration in DA-neurons of the substantia nigra’s compact (SNc) and reticular part (SNr), as well as the levels of dopamine and alpha-synuclein (total and oligomeric) in the brains of mice with a double “soft” neurotoxic model induced by the introduction of the neurotoxin 1-methyl-4-phenyl-1. This is the first time such an evaluation has been made. The presymptomatic stage of parkinsonism induced by 2,3,6-tetrahydropyridine (MPTP) involved the double administration of 12 μg/kg at a 2-hour interval, in combination with a single injection of the selective GCase inhibitor conduritol-B-epoxide (CBE) at a dose of 100 mg/kg. Additionally, we compared the transcriptomes of primary macrophage cultures from GBA-PD patients [5] with the transcriptome of SN brain tissue in model mice. We demonstrated that a singular injection of CBE resulted in a 50% decrease in GCase activity in the mouse brain and an elevation in lysosphingolipid levels. Additionally, the introduction of both MPTP and CBE led to an increase in the level of oligomeric forms of alpha-synuclein in the striatum. Simultaneously, degeneration of DA neurons in SNc, assessed by tyrosine hybroxylase (TH) immunohistochemistry 14 days after injection, was comparable to MPTP and CBE (decreasing to 50 and 60%, respectively). The neurotoxic model, when combined, demonstrates a significantly greater reduction in dopamine concentration, accumulation of total alpha-synuclein in the striatum, and more severe neurodegeneration of DA neurons in SNr (70% compared to 45% with MPTP administration). A comparison of differential gene expression in primary macrophage cultures from patients with GBA-PD and controls revealed a reduction in the expression of genes associated with neurogenesis, such as JUNB, NR4A2, and EGR1. In both the GBA-PD patient group (TRIM13, BCL6) and the MPTP-induced parkinsonism mouse group with GCase dysfunction (MPTP+CBE), genes related to the PI3K-Akt-mTOR signaling pathway, which regulates autophagy, were found to be activated. These genes include Pdk4, Sgk, and Ppp2r3d. The data obtained indicates that dysfunctional GCase leads to the accumulation of toxic forms of alpha-synuclein and degeneration of DA neurons, similar to the effects of small doses of MPTP. Combining neurotoxins (MPTP+CBE) causes a greater accumulation of alpha-synuclein and a higher degree of neuron degeneration. Transcriptomic analysis conducted on GBA-PD patients’ cells and a combined neurotoxic mouse model (MPTP+CBE) brain revealed modifications in gene expression of autophagy regulation. Approaches focused on enhancing GCase activity and autophagy exhibit potential in developing neuroprotective agents.

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confidence: 71%

Section: аннотацияunclassified

Genomic studies of neudegeneration in Parkinson’s disease associated with glucocerebrosodase dysfunction on cell and animals models

Pchelina,

Bezrukova,

Rudenok

et al. 2023

Genes & Cells

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“…Our previous study based on the comparative transcriptome analysis revealed a pronounced alteration of autophagy and immune response in GBA-PD compared to non-manifesting GBA1 mutation carriers in peripheral blood monocyte-derived macrophages [12]. Additionally, we, and others, have previously demonstrated that mutations in the GBA1 gene lead to a decrease in GCase activity in the blood in GBA1 mutation carriers independent of PD status [13][14][15][16][17]. Therefore, it is important to determine the additional modifiers that are responsible for the onset of PD in some GBA1 mutation carriers.…”

Section: Introductionmentioning

confidence: 84%

Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity

Usenko

Bezrukova

Rudenok

et al. 2023

IJMS

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Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson’s disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-β-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injection of sodium chloride (NaCl) (vehicle). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Functional clustering of differentially represented transcripts revealed more processes associated with the functioning of neurogenesis, inflammation, apoptosis and autophagy in MPTP+CBE and MPTP mice than in vehicle mice, with a more pronounced alteration of autophagy processes in MPTP+CBE mice than in MPTP mice. The PI3K-Akt-mTOR signaling pathway may be considered a potential target for therapy in PD with GCase dysfunction.

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“…In contrast, monoallelic GBA1 mutations are present in ~ 10% of the patients affected by PD, representing thus the main genetic risk for PD and linking GCase dysfunction to α-synuclein accumulation 15 . However, healthy GBA1 mutation carriers also show aberrant sphingolipids metabolism and α-synuclein accumulation 16 , 17 .…”

Section: Introductionmentioning

confidence: 99%

Tau accumulation in degradative organelles is associated to lysosomal stress

Piovesana,

Magrin,

Ciccaldo

et al. 2023

Sci Rep

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Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). The ALP is involved in the degradation of intracellular macromolecules including protein aggregates. ALP dysfunction due to inherited defects in lysosomal or non-lysosomal proteins causes a group of diseases called lysosomal storage disorders (LSD) because of abnormal accumulation of lysosomal degradation substrates. Supporting the contribution of ALP defects in neurodegenerative diseases, deposition of amyloidogenic proteins occurs in LSD. Moreover, heterozygous mutations of several ALP genes represent risk factors for Parkinson’s disease. The reciprocal contribution of α-synuclein accumulation and lysosomal dysfunction have been extensively studied. However, whether this adverse crosstalk also embraces Tau pathology needs more investigation. Here, we show in human primary fibroblasts that Tau seeds isolated from the brain of Alzheimer’s disease induce Tau accumulation in acidic degradative organelles and lysosomal stress. Furthermore, inhibition of glucocerebrosidase, a lysosomal enzyme mutated in Gaucher’s disease and a main risk for Parkinson’s disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson’s disease as well as in multiple neurodegenerative disorders including Alzheimer’s disease, our data call for further studies on strategies to alleviate ALP dysfunction as new therapeutic opportunity for neurodegenerative diseases and LSD.

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Could Blood Hexosylsphingosine Be a Marker for Parkinson's Disease Linked with GBA1 Mutations?

Cited by 9 publications

References 6 publications

Genomic studies of neudegeneration in Parkinson’s disease associated with glucocerebrosodase dysfunction on cell and animals models

Genomic studies of neudegeneration in Parkinson’s disease associated with glucocerebrosodase dysfunction on cell and animals models

Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity

Tau accumulation in degradative organelles is associated to lysosomal stress

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