Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS).
Transgenic overexpression of Cu(+2)/Zn(+2) superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (SOD1(G93A)) in a Sprague-Dawley rat results in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression, increasing from 8-fold over endogenous SOD1 in the spinal cord of young presymptomatic rats to 16-fold in end-stage animals. Disease onset in these rats was early, approximately 115 days, and disease progression was very rapid thereafter with affected rats reaching end stage on average within 11 days. Pathological abnormalities included vacuoles initially in the lumbar spinal cord and subsequently in more cervical areas, along with inclusion bodies that stained for SOD1, Hsp70, neurofilaments, and ubiquitin. Vacuolization and gliosis were evident before clinical onset of disease and before motor neuron death in the spinal cord and brainstem. Focal loss of the EAAT2 glutamate transporter in the ventral horn of the spinal cord coincided with gliosis, but appeared before motor neuron/axon degeneration. At end-stage disease, gliosis increased and EAAT2 loss in the ventral horn exceeded 90%, suggesting a role for this protein in the events leading to cell death in ALS. These transgenic rats provide a valuable resource to pursue experimentation and therapeutic development, currently difficult or impossible to perform with existing ALS transgenic mice.
Howland
David S
DS
Department of Molecular Genetics, Wyeth Research, CN8000, Princeton, NJ 08543, USA. howland@war.wyeth.com
Liu
Jian
J
She
Yijin
Y
Goad
Beth
B
Maragakis
Nicholas J
NJ
Kim
Benjamin
B
Erickson
Jamie
J
Kulik
John
J
DeVito
Lisa
L
Psaltis
George
G
DeGennaro
Louis J
LJ
Cleveland
Don W
DW
Rothstein
Jeffrey D
JD
D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D016472:Motor Neuron Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000097:blood / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013997:Time Factors
D027342:Excitatory Amino Acid Transporter 2; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1