Brca1 Is Expressed in Human Microglia and Is Dysregulated in Human and Animal Model of ALS

Mol Neurodegener. 2015 Aug 1;10:34. doi: 10.1186/s13024-015-0023-x.

Abstract

Background: 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.

Results: To 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 hSOD1(G93A) mice, the most widely used animal model of ALS. We first identified unique hSOD1(G93A) 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 hSOD1(G93A) 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.

Conclusions: Overall, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • BRCA1 Protein / biosynthesis
  • BRCA1 Protein / genetics
  • BRCA1 Protein / physiology*
  • DNA Damage
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Gliosis / genetics
  • Gliosis / pathology
  • Humans
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism*
  • Motor Neurons / metabolism
  • Mutation, Missense
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Point Mutation
  • Recombinant Proteins
  • Spinal Cord / cytology
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase-1
  • Transcriptome
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*
  • Up-Regulation

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Brca1 protein, mouse
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • SOD1 protein, human
  • Tumor Suppressor Proteins
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1