Progressive spinal axonal degeneration and slowness in ALS2-deficient mice.
OBJECTIVE
Homozygous mutation in the ALS2 gene and the resulting loss of the guanine exchange factor activity of the ALS2 protein is causative for autosomal recessive early-onset motor neuron disease that is thought to predominantly affect upper motor neurons. The goal of this study was to elucidate how the motor system is affected by the deletion of ALS2.


METHODS
ALS2-deficient mice were generated by gene targeting. Motor function and upper and lower motor neuron pathology were examined in ALS2-deficient mice and in mutant superoxide dismutase 1 (SOD1) mice that develop ALS-like disease from expression of an ALS-linked mutation in SOD1.


RESULTS
ALS2-deficient mice demonstrated progressive axonal degeneration in the lateral spinal cord that is also prominent in mutant SOD1 mice. Despite the vulnerability of these spinal axons, lower motor neurons in ALS2-deficient mice were preserved. Behavioral studies demonstrated slowed movement without muscle weakness in ALS2(-/-) mice, consistent with upper motor neuron defects that lead to spasticity in humans.


CONCLUSIONS
The combined evidence from mice and humans shows that deficiency in ALS2 causes an upper motor neuron disease that in humans closely resembles a severe form of hereditary spastic paralysis, and that is quite distinct from amyotrophic lateral sclerosis.
Yamanaka
Koji
K
Ludwig Institute for Cancer Research and Department of Medicine and Neurosciences, University of California, San Diego, La Jolla, 92093-0670, USA. kyamanaka@ucsd.edu
Miller
Timothy M
TM
McAlonis-Downes
Melissa
M
Chun
Seung Joo
SJ
Cleveland
Don W
DW
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000473:pathology; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000502:physiology; D009068:Movement; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
C512358:Als2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1