Modeling bone marrow microenvironment and hematopoietic dysregulation in Gaucher disease through VavCre mediated Gba deletion

Human Molecular Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

Abstract Biallelic mutations in Gba cause Gaucher disease (GD), a lysosomal disorder characterized by deficient glucocerebrosidase activity and the accumulation of glucosylceramide (GlcCer) glucosylsphingosine (GlcSph), primarily macrophages. Beyond macrophages, GD pathology affects additional hematopoietic lineages, contributing to immune dysregulation. Existing Mx1-Cre knockout models require induction protocols that lead gene deletion outside cells, limiting study hematopoietic-specific effects. To overcome these limitations, we generated model crossing Gbafl/fl mice with Vav-Cre, enabling early exons 8–11 stem progenitor cells. These were backcrossed 129X1/SvJ C57BL/6 J backgrounds, revealing genetic background significantly influences severity. Efficient excision was confirmed bone marrow, spleen, thymus, minimal recombination liver. In VavCre 129 mice, spleen severely reduced, leading GlcCer GlcSph cell infiltration femurs. Transcriptomic analysis identified upregulation inflammatory pathways. Immune deconvolution from RNA-seq data further revealed an expansion monocytes, dendritic pro-inflammatory macrophage subsets, suggesting altered landscape. Additionally, GPNMB, potential biomarker, elevated both spleens sera mice. This provides powerful platform for studying pathophysiology, modifier genes, It offers new opportunities biomarker discovery developing strategies targeting mechanisms related storage disorders.

Язык: Английский

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3929 - 3929

Опубликована: Апрель 1, 2024

In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on pathophysiology Parkinson’s disease (PD). line with this, alpha-syn considered to be guilty protein in process, it may targeted through precision medicine modify progression. Therefore, designing specific tools block aggregation spreading represents effort development disease-modifying therapies PD. The present article analyzes concrete evidence about significance within LBs. this effort, some dogmas are challenged. concerns question whether more abundant compared other proteins Again, occurrence non-protein constituents scrutinized. Finally, LBs causing PD questioned. These revisited concepts helpful process validating which proteins, organelles, pathways likely involved damage meso-striatal dopamine neurons brain regions

Язык: Английский

Current opinion on pluripotent stem cell technology in Gaucher's disease: challenges and future prospects

Cytotechnology, Год журнала: 2024, Номер 77(1)

Опубликована: Дек. 27, 2024

Язык: Английский