Dataset Information

A Gene Expression Phenotype In Lymphocytes From Friedreich’s Ataxia Patients

ABSTRACT: Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers, an important goal of translational research in neurodegeneration. Friedreich’s Ataxia (FRDA) is a chronic neurodegenerative disease caused by reduced transcription of frataxin, a ubiquitously expressed protein. We studied in vitro lymphocytes from FRDA patients and carriers, in order to identify a peripheral gene expression phenotype. Peripheral biomarkers related to disease status would be extremely valuable for assessing drug efficacy and could provide new pathophysiological insights. We identified a subset of genes changed in cells from patients with pathological frataxin deficiency and a core set of these genes were confirmed in independent series. Changes in gene expression were related to the mitochondria, lipid metabolism, cell cycle, and DNA repair, consistent with FRDA’s known pathophysiology. We evaluated the in vitro effect of multiple compounds (HDAC inhibitors) on this putative biomarker set, and found that this biochemical phenotype was ameliorated in accordance with drug efficacy. Frataxin downregulation is associated with robust changes in gene expression in PBMCs, providing pathogenetic insights and a core subset of genes which, if verified in vivo, could be used as a peripheral biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30933 | GEO | 2011/07/26

SECONDARY ACCESSION(S): PRJNA146285

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background Friedreich’s ataxia (FRDA) is a rare genetic disorder characterized by motor discoordination and predominant cerebellar involvement. It is caused by mutations leading to decreased transcription of frataxin (FXN), a gene encoding for a mitochondrial protein involved in the biogenesis of iron-sulfur clusters and iron handling. Many advances have been achieved in understanding the pathophysiology of FRDA and the mechanisms whereby FXN deficiency causes cerebellar degeneration. However, the issue concerning the contribution of central nervous system-resident non-neuronal cells to the pathogenesis of FRDA is still poorly explored. In this work, we set out to verify if specific vulnerabilities of cerebellar microglia could be involved in the pathogenesis of FRDA. Methods Primary cerebellar microglia were obtained from the KIKO mouse model of FRDA. We analyzed their phenotype and functions by a multilayer study, encompassing morphological analysis, migration and phagocytosis assays, gene expression by RNA-seq, RT-PCR, western blot, and immunofluorescence. Mitochondria functionality was evaluated by flow cytometry and real-time metabolic analysis. We assessed the effect of FRDA microglia on cell viability and neurite length in primary neurons. We analyzed in vivo microglia phenotype in the cerebellum of KIKO miceduring an early developmental stage by means of morphology analysis, RT-PCR and immunofluorescence. Results We demonstrated that FRDA microglia exhibit traceable morphological, transcriptional and functional changes, particularly regarding inflammatory pathways and mitochondria functionality. In addition, we found that FRDA microglia impair neuron survival and neurite length in vitro. Finally, we showed that cerebellar microglia in vivo exhibit dysregulations at early postnatal age of FRDA mice. Conclusions These results indicate that FRDA microglia display aberrant features and may participate in neuron dysfunction, evidencing a non-cell-autonomous mechanism in FRDA. Therefore, microglia targeting could be a valuable strategy in ameliorating cerebellar degeneration in the disease.

Dataset Information

A Gene Expression Phenotype In Lymphocytes From Friedreich’s Ataxia Patients

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets