Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS

Abstract

BackgroundThere is growing evidence that microglia are key players in the pathological process of amyotrophic lateral sclerosis (ALS). It is suggested that microglia have a dual role in motoneurone degeneration through the release of both neuroprotective and neurotoxic factors.ResultsTo identify candidate genes that may be involved in ALS pathology we have analysed at early symptomatic age (P90), the molecular signature of microglia from the lumbar region of the spinal cord of hSOD1G93A mice, the most widely used animal model of ALS. We first identified unique hSOD1G93A microglia transcriptomic profile that, in addition to more classical processes such as chemotaxis and immune response, pointed toward the potential involvement of the tumour suppressor gene breast cancer susceptibility gene 1 (Brca1). Secondly, comparison with our previous data on hSOD1G93A motoneurone gene profile substantiated the putative contribution of Brca1 in ALS. Finally, we established that Brca1 protein is specifically expressed in human spinal microglia and is up-regulated in ALS patients.ConclusionsOverall, our data provide new insights into the pathogenic concept of a non-cell-autonomous disease and the involvement of microglia in ALS. Importantly, the identification of Brca1 as a novel microglial marker and as possible contributor in both human and animal model of ALS may represent a valid therapeutic target. Moreover, our data points toward novel research strategies such as investigating the role of oncogenic proteins in neurodegenerative diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0023-x) contains supplementary material, which is available to authorized users.

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

“…To provide insight into the potential roles of microglia at different stages after injury, we carried out pathway analysis of DE genes in the two experimental models at the three time-points following lesion (Noristani et al, 2015b, 2016). At 72 h post-lesion, microglial responses predominantly involved proliferation as indicated by up-regulation of numerous genes involved in cell cycle processes (Table S2).…”

“…The R/Bioconductor MFuzz package v.2.18.0 was used for fuzzy clustering of the differentially expressed genes over time in both HS and FT compared to NI controls. Pathway analysis was performed using MetaCore (Thomson Reuters), as described previously (Noristani et al, 2015b, 2016). Accession number for RNA-Seq data: Gene Expression Omnibus (GE0) GSE96055.…”

“…Recent findings, including our own, using gene expression profiling in microglia have unveiled novel insights into their contribution in multiple neuropathologies (Olah et al, 2012; Parakalan et al, 2012; Beutner et al, 2013; Chiu et al, 2013; Hickman et al, 2013; Noristani et al, 2015b). To this end, using cell-specific microarrays in CD11b + microglia, we recently identified DNA damage pathway and in particular the tumor suppressor gene breast cancer susceptibility gene 1 ( Brca1 ) upregulation in an animal model of amyotrophic lateral sclerosis (ALS) (Noristani et al, 2015b). Furthermore, we identified BRCA1 as a novel human microglial marker and demonstrated its specific over-expression in ALS microglia within the spinal cord (Noristani et al, 2015b).…”

“…To this end, using cell-specific microarrays in CD11b + microglia, we recently identified DNA damage pathway and in particular the tumor suppressor gene breast cancer susceptibility gene 1 ( Brca1 ) upregulation in an animal model of amyotrophic lateral sclerosis (ALS) (Noristani et al, 2015b). Furthermore, we identified BRCA1 as a novel human microglial marker and demonstrated its specific over-expression in ALS microglia within the spinal cord (Noristani et al, 2015b). …”

The immunogenetics of neurological disease

“…The roles of microglia in several neurological diseases are well documented. [26][27][28] Taken together, the HLA loci are vital for shaping cellular adaptive immune responsiveness, and their impact upon human health and disease has long been appreciated. During the course of four decades, the impact of variation in HLA has been studied with respect to neurological disease.…”