Biology subjects

Frucht, S.

Publications and source records attributed to Frucht, S..

3 recordsLinked to original sources

bioRxiv2024

LRRK2 G2019S variant is associated with transcriptional changes in Parkinson's disease human myeloid cells under proinflammatory environment

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinsons disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFN{gamma} and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFN{gamma} stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.

genetics↗

bioRxiv2020

Discordant transcriptional signatures of mitochondrial genes in Parkinson's disease human myeloid cells

An increasing number of identified Parkinsons disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their potential role in pathological mechanisms is not obvious. We have generated transcriptomic profiles of CD14+ monocytes from 230 individuals with sporadic PD and age-matched healthy subjects. We identified dysregulation of genes involved in mitochondrial and proteasomal function. We also generated transcriptomic profiles of primary microglia from autopsied brains of 55 PD and control subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified PD susceptibility genes, whose expression, relative to each risk allele, is altered in monocytes. These findings reveal that transcriptomic mitochondrial alterations are detectable in PD monocytes and are distinct from brain microglia, and facilitates efforts to understand the roles of myeloid cells in PD.

neuroscience↗

bioRxiv2019

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease and progressive supranuclear palsy converge on altered glial regulation

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble -synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with -synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

neuroscience↗