Host: The Physiological Society of Japan
Dominant mutations in the ubiquitously expressed Cu/Zn superoxide dismutase (SOD1) lead to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motor neurons. Although ubiquitous expression of mutant SOD1 provokes progressive, selective motor neuron degeneration in human and rodents due to an acquired toxic property(ies) of the mutant, the cell types that contribute to the onset and progression of the motor neuron disease are not known. To test whether mutant SOD1 toxicity within specific cell types contributes to motor neuron degeneration, we have generated a mouse ubiquitously expressing a "floxed" mutant SOD1 transgene (LoxSOD1G37R) which can be removed within specific cell populations by the action of Cre recombinase. To eliminate mutant SOD1 within motor neurons or non-neuronal cells, Lox SOD1G37R mice were mated to Islet1-Cre, CD11b-Cre, or GFAP-Cre that express Cre specifically in motor neurons, microglia, or astrocytes, respectively. Removing mutant SOD1 from motor neurons slowed the timing of disease onset and early disease progression, indicating mutant action in neurons as an initiating factor in triggering disease. More importantly, silencing of SOD1 mutant expression selectively within microglial cells or astrocytes has minimal effect on age of disease onset, but sharply slows disease progression. Thus, onset and progression represent distinct disease phases defined by mutant action within different cell types to generate non-cell-autonomous killing of motor neurons, findings that validate therapies, including cell replacement, targeted to the glial cells. [J Physiol Sci. 2008;58 Suppl:S11]
