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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2015

Open Access 01-12-2015 | Research article

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

Authors: Harun Najib Noristani, Jean Charles Sabourin, Yannick Nicolas Gerber, Marisa Teigell, Andreas Sommacal, Maria dM Vivanco, Markus Weber, Florence Evelyne Perrin

Published in: Molecular Neurodegeneration | Issue 1/2015

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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 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.

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.
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Literature
1.
Leblond CS, Kaneb HM, Dion PA, Rouleau GA. Dissection of genetic factors associated with amyotrophic lateral sclerosis. Exp Neurol. 2014;262 Pt B:91–101.PubMedCrossRef
2.
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5.PubMedCrossRef
3.
Philips T, Rothstein JD. Glial cells in amyotrophic lateral sclerosis. Exp Neurol. 2014;262 Pt B:111–20.PubMedCrossRef
4.
Crain JM, Nikodemova M, Watters JJ. Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. J Neurosci Res. 2013;91:1143–51.PubMedCentralPubMedCrossRef
5.
Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol. 2009;210:3–12.PubMedCrossRef
6.
7.
Gerber YN, Sabourin JC, Rabano M, Vivanco M, Perrin FE. Early functional deficit and microglial disturbances in a mouse model of amyotrophic lateral sclerosis. PLoS One. 2012;7, e36000.PubMedCentralPubMedCrossRef
8.
Perrin FE, Boisset G, Docquier M, Schaad O, Descombes P, Kato AC. No widespread induction of cell death genes occurs in pure motoneurons in an amyotrophic lateral sclerosis mouse model. Hum Mol Genet. 2005;14:3309–20.PubMedCrossRef
9.
Perrin FE, Boisset G, Lathuiliere A, Kato AC. Cell death pathways differ in several mouse models with motoneurone disease: analysis of pure motoneurone populations at a presymptomatic age. J Neurochem. 2006;98:1959–72.PubMedCrossRef
10.
11.
Caestecker KW, Van de Walle GR. The role of BRCA1 in DNA double-strand repair: past and present. Exp Cell Res. 2013;319:575–87.PubMedCrossRef
12.
Somasundaram K. Breast cancer gene 1 (BRCA1): role in cell cycle regulation and DNA repair–perhaps through transcription. J Cell Biochem. 2003;88:1084–91.PubMedCrossRef
13.
Savage KI, Harkin DP. BRCA1, a ‘complex’ protein involved in the maintenance of genomic stability. FEBS J. 2015;282:630–46.PubMedCrossRef
14.
Bae I, Fan S, Meng Q, Rih JK, Kim HJ, Kang HJ, et al. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res. 2004;64:7893–909.PubMedCrossRef
15.
Vurusaner B, Poli G, Basaga H. Tumor suppressor genes and ROS: complex networks of interactions. Free Radic Biol Med. 2012;52:7–18.PubMedCrossRef
16.
Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO. Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol. 2008;39:857–65.PubMedCrossRef
17.
Bernard-Gallon DJ, De Latour MP, Sylvain V, Vissac C, Aunoble B, Chassagne J, et al. Brca1 and Brca2 protein expression patterns in different tissues of murine origin. Int J Oncol. 2001;18:271–80.PubMed
18.
Korhonen L, Brannvall K, Skoglosa Y, Lindholm D. Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation. J Neurosci Res. 2003;71:769–76.PubMedCrossRef
19.
Gerber YN, Sabourin JC, Hugnot JP, Perrin FE. Unlike physical exercise, modified environment increases the lifespan of SOD1G93A mice however both conditions induce cellular changes. PLoS One. 2012;7, e45503.PubMedCentralPubMedCrossRef
20.
21.
Liao B, Zhao W, Beers DR, Henkel JS, Appel SH. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol. 2012;237:147–52.PubMedCentralPubMedCrossRef
22.
Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16:1896–905.PubMedCrossRef
23.
Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP, et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013;4:385–401.PubMedCentralPubMedCrossRef
24.
Beers DR, Zhao W, Liao B, Kano O, Wang J, Huang A, et al. Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice. Brain Behav Immun. 2011;25:1025–35.PubMedCentralPubMedCrossRef
25.
Liu B, Li D, Guan YF. BRCA1 regulates insulin-like growth factor 1 receptor levels in ovarian cancer. Oncol Lett. 2014;7:1733–7.PubMedCentralPubMed
26.
Werner H, Bruchim I. IGF-1 and BRCA1 signalling pathways in familial cancer. Lancet Oncol. 2012;13:e537–44.PubMedCrossRef
27.
Henkel JS, Beers DR, Zhao W, Appel SH. Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol. 2009;4:389–98.PubMedCrossRef
28.
David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011;12:388–99.PubMedCrossRef
29.
Mantha AK, Sarkar B, Tell G. A short review on the implications of base excision repair pathway for neurons: relevance to neurodegenerative diseases. Mitochondrion. 2014;16:38–49.PubMedCrossRef
30.
Pulvers JN, Huttner WB. Brca1 is required for embryonic development of the mouse cerebral cortex to normal size by preventing apoptosis of early neural progenitors. Development. 2009;136:1859–68.PubMedCrossRef
31.
32.
Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet. 1996;12:191–4.PubMedCrossRef
33.
King TM, Au KS, Kirkpatrick TJ, Davidson C, Fletcher JM, Townsend I, et al. The impact of BRCA1 on spina bifida meningomyelocele lesions. Ann Hum Genet. 2007;71:719–28.PubMedCrossRef
34.
Evans TA, Raina AK, Delacourte A, Aprelikova O, Lee HG, Zhu X, et al. BRCA1 may modulate neuronal cell cycle re-entry in Alzheimer disease. Int J Med Sci. 2007;4:140–5.PubMedCentralPubMedCrossRef
35.
Nakanishi A, Minami A, Kitagishi Y, Ogura Y, Matsuda S. BRCA1 and p53 tumor suppressor molecules in Alzheimer’s disease. Int J Mol Sci. 2015;16:2879–92.PubMedCentralPubMedCrossRef
36.
Jeon GS, Kim KY, Hwang YJ, Jung MK, An S, Ouchi M, et al. Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of gamma-H2AX and DNA damage responses in Huntington’s disease. Mol Neurobiol. 2012;45:550–63.PubMedCrossRef
37.
Brain L, Croft PB, Wilkinson M. Motor neurone disease as a manifestation of neoplasm (with a note on the course of classical motor neurone disease). Brain. 1965;88:479–500.PubMedCrossRef
38.
Chio A, Brignolio F, Meineri P, Rosso MG, Tribolo A, Schiffer D. Motor neuron disease and malignancies: results of a population-based study. J Neurol. 1988;235:374–5.PubMedCrossRef
39.
Forsyth PA, Dalmau J, Graus F, Cwik V, Rosenblum MK, Posner JB. Motor neuron syndromes in cancer patients. Ann Neurol. 1997;41:722–30.PubMedCrossRef
40.
Rojas-Marcos I, Rousseau A, Keime-Guibert F, Rene R, Cartalat-Carel S, Delattre JY, et al. Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer. Medicine. 2003;82:216–23.PubMed
41.
Sadot E, Carluer L, Corcia P, Delozier Y, Levy C, Viader F. Breast cancer and motor neuron disease: clinical study of seven cases. Amyotroph Lateral Scler. 2007;8:288–91.PubMedCrossRef
42.
Berghs S, Ferracci F, Maksimova E, Gleason S, Leszczynski N, Butler M, et al. Autoimmunity to beta IV spectrin in paraneoplastic lower motor neuron syndrome. Proc Natl Acad Sci U S A. 2001;98:6945–50.PubMedCentralPubMedCrossRef
43.
Evans BK, Fagan C, Arnold T, Dropcho EJ, Oh SJ. Paraneoplastic motor neuron disease and renal cell carcinoma: improvement after nephrectomy. Neurology. 1990;40:960–2.PubMedCrossRef
44.
Forman D, Rae-Grant AD, Matchett SC, Cowen JS. A reversible cause of hypercapnic respiratory failure: lower motor neuronopathy associated with renal cell carcinoma. Chest. 1999;115:899–901.PubMedCrossRef
45.
Kiewe P, Gueller S, Komor M, Stroux A, Thiel E, Hofmann WK. Prediction of qualitative outcome of oligonucleotide microarray hybridization by measurement of RNA integrity using the 2100 Bioanalyzer capillary electrophoresis system. Ann Hematol. 2009;88:1177–83.PubMedCrossRef
46.
Hubbell E, Liu WM, Mei R. Robust estimators for expression analysis. Bioinformatics. 2002;18:1585–92.PubMedCrossRef
47.
Liu WM, Mei R, Di X, Ryder TB, Hubbell E, Dee S, et al. Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics. 2002;18:1593–9.PubMedCrossRef
48.
Noristani HN, Olabarria M, Verkhratsky A, Rodriguez JJ. Serotonin fibre sprouting and increase in serotonin transporter immunoreactivity in the CA1 area of hippocampus in a triple transgenic mouse model of Alzheimer’s disease. Eur J Neurosci. 2010;32:71–9.PubMedCrossRef
Metadata
Title
Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS
Authors
Harun Najib Noristani
Jean Charles Sabourin
Yannick Nicolas Gerber
Marisa Teigell
Andreas Sommacal
Maria dM Vivanco
Markus Weber
Florence Evelyne Perrin
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2015
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-015-0023-x

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