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

David R. Beers, Jenny S. Henkel, Qin Xiao, Weihua Zhao, Jinghong Wang, Albert A. Yen, Laszlo Siklos, Scott R. McKercher, Stanley H. Appel

Research output: Contribution to journalArticlepeer-review

604 Scopus citations


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 (mSOD1G93A) 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 mSOD1G93A in motoneurons and astroglia, as well as microglia, was required to produce motoneuron disease, PU.1-/- mice were bred with mSOD1G93A mice. In mSOD1G93A/PU.1-/- mice, wild-type donor-derived microglia slowed motoneuron loss and prolonged disease duration and survival when compared with mice receiving mSOD1G93A expressing cells or mSOD1 G93A mice. In vitro studies confirmed that wild-type microglia were less neurotoxic than similarly cultured mSOD1G93A microglia. Compared with wild-type microglia, mSOD1G93A microglia produced and released more superoxide and nitrite+nitrate, and induced more neuronal death. These data demonstrate that the expression of mSOD1G93A results in activated and neurotoxic microglia, and suggests that the lack of mSOD1G93A 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.

Original languageEnglish (US)
Pages (from-to)16021-16026
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
StatePublished - Oct 24 2006


  • Bone marrow transplant
  • Motoneurons
  • Neuroprotection
  • Nitric oxide
  • Superoxide dismutase

ASJC Scopus subject areas

  • Genetics
  • General


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