Abstract:
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Since its description by Charcot in 1869, the mechanism of selective death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) has remained elusive. An inherited form is caused by mutation in superoxide dismutase (SOD1) that causes disease from an acquired toxicity unrelated to dismutase activity. Using mice carrying a deletable mutant gene or viral encoded siRNA to diminish mutant expression within motor neurons, disease onset is slowed but progression is not. Conversely, reducing mutant SOD1 synthesis in microglia has little effect on disease onset, but strikingly slows disease progression. Diminished mutant expression in astrocytes also does not affect onset, but delays microglial activation and recruitment and sharply slows later disease progression. Mutant damage within muscle does not play a significant role and sustained increases in muscle mass and myofiber number (by AAV-encoded expression of follistatin to chronically inhibit myostatin) do not affect disease course. Damage within cells other than motor neurons does contribute to disease onset. The presence of wild type non-motor neurons delays motor neuron disease in chimeric mice that have high-level mutant expression within 100% of motor neurons, implicating a central role of mutant SOD1 damage within non-motor neurons in initiating motor neuron degeneration. Damaged non-neuronal cells implicated in disease onset include endothelial cells of the vasculature. Mutant-dependent microhemorrhages, accompanied by loss of capillary length and reduced blood flow within the spinal cord, initiate well before motor neuron degeneration. Thus, toxicity is non-cell autonomous, with mutant SOD1 acting within motor neurons (and possibly vascular endothelial cells) driving disease onset, while damage within neighboring astrocytes and microglia accelerates disease progression. These findings validate therapies, including microglial or astrocytic stem cell replacement approaches, to slow disease progression in ALS by supplementing healthy astrocytes or modulating the toxicity within astrocytes to control an inflammatory response of microglia.
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