Biology subjects

Udine, E.

Publications and source records attributed to Udine, E..

5 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↗

bioRxiv2023

Differential neuronal vulnerability to C9orf72 repeat expansion driven by Xbp1 transcription signature

A G4C2 repeat expansion in the gene C9orf72 (C9) is the most common genetic cause of sporadic and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). What determines why cell death is triggered only in specific neuronal populations, while others remain protected or are less susceptible to disease is still an open question. In particular, whether it is the transcriptional response to the accumulation of toxic insults or the initial cellular state that determines their vulnerability is still unknown. We have carried out a large-scale profiling of single cell transcriptional signatures throughout disease development in a Drosophila model of C9 repeat toxicity. This enabled us to monitor transcriptional shifts and track changes in cell populations during disease progression. We have identified neuronal populations which are depleted in response to C9 repeat expression, and therefore vulnerable to toxicity. On the other hand, other neuron types are resistant to toxicity, and maintain their cell number during disease progression. Our findings suggest that a major determinant of vulnerability is the transcriptional state of the cell before it is exposed to C9 repeat expression. We have identified a conserved transcriptional profile that is associated with resistance to C9 repeat toxicity. Neurons resistant to disease display a higher expression of genes involved in protein homeostasis, with Xbp1 identified as a crucial transcription factor determining neuronal vulnerability.

neuroscience↗

bioRxiv2023

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of ALS and FTD (C9ALS/FTD). The presence of dipeptide repeat (DPR) proteins, generated by translation of the expanded repeat, is a major pathogenic feature of C9ALS/FTD pathology, but their most relevant effects in a physiological context are not known. Here, we generated C9orf72 DPR knock-in mouse models characterised by physiological expression of 400 codon-optimised polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice exhibit cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction, showing that they recapitulate key features of C9FTD/ALS. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. This signature of increased ECM proteins was also present in C9ALS patient iPSC-motor neurons indicating it is a conserved feature of C9ALS/FTD. TGF-{beta}1 was one of the top predicted regulators of this ECM signature and polyGR expression in human iPSC-neurons was sufficient to induce TGF-{beta}1 followed by COL6A1, indicating TGF-{beta}1 is one driver of the ECM signature. Knockdown of the TGF-{beta}1 or COL6A1 orthologue in Drosophila dramatically and specifically exacerbated neurodegeneration in polyGR flies, showing that TGF-{beta}1 and COL6A1 protect against polyGR toxicity. Altogether, our physiological C9orf72 DPR knock-in mice have revealed a neuroprotective and conserved ECM signature in C9FTD/ALS.

neuroscience↗

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↗

bioRxiv2018

Tensor Decomposition of Stimulated Monocyte and Macrophage Gene Expression Profiles Identifies Neurodegenerative Disease-specific Trans-eQTLs

Recent human genetic studies suggest that cells of the innate immune system have a primary role in the pathogenesis of neurodegenerative diseases. However, the results from these studies often do not elucidate how the genetic variants affect the biology of these cells to modulate disease risk. Here, we applied a tensor decomposition method to uncover disease-associated gene networks linked to distal genetic variation in stimulated human monocytes and macrophages gene expression profiles. We report robust evidence that some disease-associated genetic variants affect the expression of multiple genes in trans. These include a Parkinsons disease locus influencing the expression of genes mediated by a protease that controls lysosomal function, and Alzheimers disease loci influencing the expression of genes involved in type 1 interferon signaling, myeloid phagocytosis, and complement cascade pathways. Overall, we uncover gene networks in induced innate immune cells linked to disease-associated genetic variants, which may help elucidate the underlying biology of disease.

genomics↗