GBA1MUTATIONS ALTER THE PHENOTYPE AND BEHAVIOUR OF DOPAMINERGIC NEURONS IN PARKINSON’S DISEASE, INFLUENCINGVGLUT2ANDCRYABEXPRESSION

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 7, 2024

Abstract Mutations in the GBA1 gene are major risk factors for Parkinsońs disease (PD), but their role PD pathology is not fully understood. The impact of mutations was investigated dopamine (DA) neurons obtained from induced pluripotent stem cells (iPSCs) derived patients carrying N370S or L444P mutation. DA co-expressing TH and VGLUT2 were detected cultures, number and/or expression / SLC17A6 mRNA markedly reduced both cultures compared to controls. A significant increase firing rate found, whereas evoked release stronger either Furthermore, mutant accumulated abundant degenerative structures, there a accumulation α-synuclein aggregates neurons. Notably, upregulation chaperone CRYAB/HSPB5/alpha-crystallin-B found early neuron differentiation substantia nigra patients. Our findings indicate that impair midbrain expressing VGLUT2, provoke molecular, functional structural changes, possibly involved pathology.

Язык: Английский

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Lipids and α-Synuclein: adding further variables to the equation

Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11

Опубликована: Авг. 12, 2024

Graphical Abstract The graphical abstract summarises factors that might lead to lipid changes and possible influences of on synucleinopathies.

Язык: Английский

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GBA1 mutations alter neuronal excitability and ultrastructure in Parkinson´s disease, regulating VGLUT2 and CRYAB in dopaminergic neurons

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Дек. 16, 2024

Mutations in the glucocerebrosidase 1 (GBA1) gene are major risk factors for Parkinson´s disease (PD), but their role PD etiopathology is not fully understood. The impact of GBA1 mutations on neuronal maturation, function and degeneration was investigated dopaminergic (DA) neurons obtained from induced pluripotent stem cells (iPS cells/iPSCs) derived patients carrying heterozygous N370S or L444P mutation GBA1. DA co-expressing TH VGLUT2 were detected cultures, number and/or expression VGLUT2/SLC17A6 mRNA markedly reduced both cultures compared to controls. Electrophysiological recordings revealed a significant increase firing rate neurons, whereas evoked dopamine release stronger either than Furthermore, there accumulation α-synuclein aggregates cell body dendrites neurons. Remarkably, accumulated abundant Lewy body-like inclusions, multilamellar bodies, Golgi apparatus vacuolated dictyosomes autophagosomes. Notably, upregulation chaperone CRYAB/HSPB5/alpha-crystallin-B found early neuron differentiation substantia nigra patients. Therefore, our cellular model allows clear features neurodegeneration be Our findings indicate that impair midbrain expressing VGLUT2, provoke molecular, functional ultrastructural changes, possibly involved etiopathology. They suggest CRYAB may potentially serve as molecular targets biomarkers GBA1-PD.

Язык: Английский

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Expression Profiles of TRIM Family Genes in Neuronal and Glial Cell Cultures of Healthy Donors and Patients with Parkinson’s Disease under Normal Conditions and Upon Neuroinflammation

Molecular Biology, Год журнала: 2024, Номер 58(6), С. 1208 - 1218

Опубликована: Дек. 1, 2024

Язык: Английский

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