Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis

doi:10.1073/pnas.0607423103

Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis

*Department of Neurology, Methodist Neurological Institute, Houston, TX 77030;
^†Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, People's Republic of China;
^‡Institute of Biophysics, Biological Research Center, H-6726, Szeged, Hungary; and
^§Burnham Institute for Medical Research, Del E. Web Center for Neurosciences and Aging, La Jolla, CA 92037

Communicated by Salih J. Wakil, Baylor College of Medicine, Houston, TX, September 1, 2006 (received for review June 7, 2006)

Abstract

The most common inherited form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motoneurons, is caused by dominant mutations in the ubiquitously expressed Cu²⁺/Zn²⁺ superoxide dismutase (SOD1). Recent studies suggest that glia may contribute to motoneuron injury in animal models of familial ALS. To determine whether the expression of mutant SOD1 (mSOD1^G93A) in CNS microglia contributes to motoneuron injury, PU.1^−/− mice that are unable to develop myeloid and lymphoid cells received bone marrow transplants resulting in donor-derived microglia. Donor-derived microglia from mice overexpressing mSOD1^G93A, an animal model of familial ALS, transplanted into PU.1^−/− mice could not induce weakness, motoneuron injury, or an ALS-like disease. To determine whether expression of mSOD1^G93A in motoneurons and astroglia, as well as microglia, was required to produce motoneuron disease, PU.1^−/− mice were bred with mSOD1^G93A mice. In mSOD1^G93A/PU.1^−/− mice, wild-type donor-derived microglia slowed motoneuron loss and prolonged disease duration and survival when compared with mice receiving mSOD1^G93A expressing cells or mSOD1^G93A mice. In vitro studies confirmed that wild-type microglia were less neurotoxic than similarly cultured mSOD1^G93A microglia. Compared with wild-type microglia, mSOD1^G93A microglia produced and released more superoxide and nitrite+nitrate, and induced more neuronal death. These data demonstrate that the expression of mSOD1^G93A results in activated and neurotoxic microglia, and suggests that the lack of mSOD1^G93A expression in microglia may contribute to motoneuron protection. This study confirms the importance of microglia as a double-edged sword, and focuses on the importance of targeting microglia to minimize cytotoxicity and maximize neuroprotection in neurodegenerative diseases.

Footnotes

^¶To whom correspondence should be addressed. E-mail: sappel{at}tmh.tmc.edu
Author contributions: D.R.B. and J.S.H. contributed equally to this work; D.R.B., J.S.H., and S.H.A. designed research; D.R.B., J.S.H., Q.X., W.Z., J.W., and L.S. performed research; S.R.M. contributed new reagents/analytic tools; D.R.B., J.S.H., and A.A.Y. analyzed data; and D.R.B. and J.S.H. wrote the paper.
The authors declare no conflict of interest.
↵ ‖ Joarsma, D., Teuling, E., Hoogenraad, C. C. (2006) Soc. Neurosci. Abstr. 36, abstr. 508.1 (abstr.).
Abbreviations:

ALS,

amyotrophic lateral sclerosis;

BMT,

bone marrow transplant.
Freely available online through the PNAS open access option.