Onset and progression in inherited ALS determined by motor neurons and microglia.
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.
Boillée
Séverine
S
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.
Yamanaka
Koji
K
Lobsiger
Christian S
CS
Copeland
Neal G
NG
Jenkins
Nancy A
NA
Kassiotis
George
G
Kollias
George
G
Cleveland
Don W
DW
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D039481:CD11b Antigen / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D039481:CD11b Antigen; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C045073:Cre recombinase; D019426:Integrases