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.
Highlights
There is growing evidence that microglia are key players in the pathological process of amyotrophic lateral sclerosis (ALS)
In ALS patients and animal models, there is a clear microglia activation [3], in particular we have shown an early involvement of microglia in hSOD1G93A mice [7]
Transcriptomic analysis of fluorescenceactivated cell sorting (FACS) isolated microglia from control and hSOD1G93A lumber spinal cord We have previously described early microglial disturbances in hSOD1G93A male mice reflected at P90 by a heterogeneous Iba1+ microglial distribution with higher density within the grey matter in hSOD1G93A mice as compared to control [7, 19]
Summary
There 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. Amyotrophic lateral sclerosis (ALS) is characterised by selective motoneurones degeneration in the spinal cord, brainstem and motor cortex leading to progressive muscle weakness, atrophy and paralysis. Transgenic mice over-expressing the human mutated gene for SOD1 develop an adult-onset paralysis that closely recapitulates human ALS [2]. Microglia have a dual role in ALS with an early protective effect on motoneurones and a detrimental effect due to the secretion of neurotoxic factors [6]. One means of analysing the role of a cell population in a process network is to study gene expression alterations in this given population.
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