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PNAS 110 (10): 4069-4074

Copyright © 2013 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

Reactive astrocytes secrete lcn2 to promote neuron death

Fangfang Bia,b,1, Cao Huanga,1, Jianbin Tonga,1, Guang Qiua,1, Bo Huangb, Qinxue Wua, Fang Lia, Zuoshang Xuc, Robert Bowserd, Xu-Gang Xiaa,2, and Hongxia Zhoua,b,2

Departments of aPathology, Anatomy, and Cell Biology, and bNeurology, Thomas Jefferson University, Philadelphia, PA 19107; cDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605; and dDivisions of Neurology and Neurobiology, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013

Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved January 17, 2013 (received for review October 23, 2012)

Abstract: Glial reaction is a common feature of neurodegenerative diseases. Recent studies have suggested that reactive astrocytes gain neurotoxic properties, but exactly how reactive astrocytes contribute to neurotoxicity remains to be determined. Here, we identify lipocalin 2 (lcn2) as an inducible factor that is secreted by reactive astrocytes and that is selectively toxic to neurons. We show that lcn2 is induced in reactive astrocytes in transgenic rats with neuronal expression of mutant human TAR DNA-binding protein 43 (TDP-43) or RNA-binding protein fused in sarcoma (FUS). Therefore, lcn2 is induced in activated astrocytes in response to neurodegeneration, but its induction is independent of TDP-43 or FUS expression in astrocytes. We found that synthetic lcn2 is cytotoxic to primary neurons in a dose-dependent manner, but is innocuous to astrocytes, microglia, and oligodendrocytes. Lcn2 toxicity is increased in neurons that express a disease gene, such as mutant FUS or TDP-43. Conditioned medium from rat brain slice cultures with neuronal expression of mutant TDP-43 contains abundant lcn2 and is toxic to primary neurons as well as neurons in cultured brain slice from WT rats. Partial depletion of lcn2 by immunoprecipitation reduced conditioned medium-mediated neurotoxicity. Our data indicate that reactive astrocytes secrete lcn2, which is a potent neurotoxic mediator.

Key Words: amyotrophic lateral sclerosis • astrocytosis

Author contributions: F.B., C.H., J.T., G.Q., B.H., X.-G.X., and H.Z. designed research; F.B., C.H., J.T., G.Q., B.H., Q.W., F.L., and H.Z. performed research; Z.X. and R.B. contributed new reagents/analytic tools; F.B., C.H., J.T., G.Q., B.H., Q.W., F.L., X.-G.X., and H.Z. analyzed data; and F.B., C.H., J.T., Z.X., X.-G.X., and H.Z. wrote the paper.

1F.B., C.H., J.T., and G.Q. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1218497110/-/DCSupplemental.

2To whom correspondence may be addressed. E-mail: xugang.xia{at}jefferson.edu or hongxia.zhou{at}jefferson.edu.

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