Quantitative immunocytochemical analysis of the spinal cord in G86R superoxide dismutase transgenic mice: Neurochemical correlates of selective vulnerability

Abstract

Transgenic mice with a G86R mutation in the mouse superoxide dismutase (SOD-1) gene, which corresponds to a mutation that has been observed in familial amyotrophic lateral sclerosis (ALS), display progressive loss of motor function and provide a valuable model of ALS. The pathology in the spinal cords of these mice was evaluated to determine whether there are chemically identified populations of neurons that are either highly vulnerable or resistant to degeneration. Qualitatively, there were phosphorylated neurofilament protein (NFP)-immunoreactive inclusions and a pronounced loss of motoneurons in the ventral horn of the spinal cord without the presence of vacuoles that has been reported in other SOD-1 transgenic mice. Neuron counts from SOD-1 and control spinal cords revealed that the percentage loss of NFP-, choline acetyltransferase (ChAT)-, and calretinin (CR)-immunoreactive neurons was greater than the percentage loss of total neurons, suggesting that these neuronal groups are particularly vulnerable in SOD-1 transgenic mice. In contrast, calbindin-containing neurons did not degenerate significantly and represent a protected population of neurons. Quantitative double-labeling experiments suggested that the vulnerability of ChAT- and CR-immunoreactive neurons was due primarily to the presence of NFP within a subset of these neurons, which degenerated preferentially to ChAT- and CR-immunoreactive neurons that did not colocalize with NFP. Our findings suggest that NFP, which has been demonstrated previously to be involved mechanistically in motoneuron degeneration, may also be important in the mechanism of degeneration that is initiated by the SOD-1 mutation.

Lithium delays progression of amyotrophic lateral sclerosis

“…Studies in animal models or in vitro led to the identification of a variety of alterations in ALS motor neurons (MN) (1,3,4); however, other cells in the spinal cord besides MN are affected (5)(6)(7)(8). For instance, a class of interneurons die either before or concomitantly with MN, as found in mice (9,10) and postulated in humans for Renshaw-like cells (11). Again, glial cells participate in the deleterious interplay leading to MN degeneration (6)(7)(8).…”

Exacerbation of Motor Neuron Disease by Chronic Stimulation of Innate Immunity in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Transgenic mice expressing mutant SOD1 develop motor neuron disease resembling ALS, through a gain of unidentified deleterious properties (Wong et al, 1995;Bruijn et al, 1997). Several mechanisms have been proposed to account for such toxicity including excitotoxicity (Bruijn et al, 1997), disruption of the calcium homeostasis (Morrison et al, 1996;Roy et al, 1998), cytoskeletal abnormalities (Wong et al, 1995), Fas ligand (FasL)-mediated death (Raoul et al, 2002), and deregulation of Cdk5 (cyclin-dependent kinase 5) (Nguyen et al, 2001a).…”

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

“…SOD1 G85R transgenic mice expressing mutant SOD1 as little as 20% of endogenous levels also develop neuromuscular disease characterized by loss of large motor neurons in brainstem and in spinal cord (10,17). No vacuolization has been reported in G85R mice or in similar mice expressing the murine counterpart mutation G86R (18,24). However, these mice also develop cytoplasmic inclusions that appear in astrocytes and neurons before clinical signs of disease and dramatically increase in abundance with disease progression (10).…”