Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions.

Abstract

(16,17). To gain further insights into the pathogenesis of FALS, the studies described in this paper were designed to characterize alterations in the neuronal cytoskeleton in the G1H mice and to compare these alterations with those seen in human ALS.MATERIALS AND METHODS Generation of Human SOD1 Transgenic Mice. The G1H line of transgenic mice carry a human SOD1 gene with a Gly-93 -> Ala substitution (G93A). These derive from a described Gl line (13) and have a 40% expansion in transgene copy number (P. Zhai and M.E.G., unpublished data). The G1H mice have been deposited with the Induced Mutant Resource maintained by The Jackson Laboratory (Bar Harbor, ME) under the strain designation C57BL/6J-TgN(SOD1-G93A)lGur. The N1029

Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1

“…Nonetheless, there was induction of Cdk2 in glial cells from the spinal cord of SOD1 G37R mice ( Fig. 1 H, white arrowheads), which is compatible with the gliosis and inflammation occurring in these mice (Wong et al, 1995;Tu et al, 1996;Bruijn et al, 1997;Morrison et al, 1998;Nguyen et al, 2001b). The involvement of Cdk1, Cdk2, and Cdk3 in proliferation of glial cells is further supported by the PSTAIRE immunoreactivities detected in glial cells of the spinal cord from SOD1 G37R mice ( Fig.…”

“…The SOD1 protein is a cytosolic free radical scavenging metalloenzyme protecting cells from oxidative stress (Fridovich, 1986). Transgenic mice expressing mutant SOD1 develop motor neuron disease resembling ALS, through a gain of unidentified deleterious properties (Gurney et al, 1994;Wong et al, 1995;Tu et al, 1996;Bruijn et al, 1997Bruijn et al, , 1998Morrison et al, 1998). Several mechanisms have been proposed to account for such toxicity, including oxidation-and nitration-related damages, protein aggregation, excitotoxicity, inflammation, mitochondrial damage, disturbance of calcium homeostasis, and aberrant phosphorylation by deregulated Cdk5.…”

Intrathecal infusion of a Ca2+-permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter, GLT-1 in a mutant SOD1 rat model of ALS

“…Previous reports have indicated progressive reactive astrogliosis, nitrotyrosine labeling and loss of astrocytic glutamate transport in SOD1 mutant rodent models of ALS (Alexander et al, 2000;Ferrante et al, 1997;Tu et al, 1996), and a specific decrease of the GLT-1 glutamate transporter has been reported in ventral horn of the G93A rats that are the subject of this study (Howland et al, 2002). Consistent with these prior studies we see a dramatic increase in astrogliosis, as indicated by GFAP labeling, most prominent initially in ventral horn, and extending throughout the gray matter of the spinal cord by the onset of symptoms (Fig 2A, 3).…”

Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS)

“…4c), suggesting mutant-dependent depletion of the intracellular protein folding chaperone pool. Aberrant accumulations of neurofilaments, reported in SOD1 G93A -expressing transgenic mice (29), were prominent abnormalities after disease onset, both in perikarya (Fig. 4d) and in distended axonal swellings [compare the neurofilament staining in transgenic axons ( Fig.…”