Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia
Séverine Boillée,1*
Koji Yamanaka,1*
Christian S. Lobsiger,1
Neal G. Copeland,2
Nancy A. Jenkins,2
George Kassiotis,3
George Kollias,3
Don W. Cleveland1
Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression. Onset and progression thus represent distinct disease phases defined by mutant action within different cell types to generate non–cell-autonomous killing of motor neurons; these findings validate therapies, including cell replacement, targeted to the non-neuronal cells.
1 Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2 Mouse Cancer Genetics Program, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
3 Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, 166 72 Vari, Greece.
* These authors contributed equally to this work.
Present address: Division of Immunoregulation, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
To whom correspondence should be addressed. E-mail: dcleveland{at}ucsd.edu (D.W.C.); kyamanaka{at}ucsd.edu (K.Y.)
