Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive paralysis arising from the premature death of motor neurons. An inherited form is caused by a dominant mutation in the ubiquitously expressed superoxide dismutase (SOD1). SOD1 mutant expression within motor neurons is a determinant of onset and early disease, and mutant accumulation within microglia accelerates disease progression. Muscle also is a likely primary source for toxicity, because retraction of motor axons from synaptic connections to muscle is among the earliest presymptomatic events. To test involvement of muscle in ALS, viral delivery of transcriptionmediated siRNA is shown to suppress mutant SOD1 accumulation within muscle alone but to be insufficient to maintain grip strength, whereas delivery to both motor neurons and muscle is sufficient. Use of a deletable mutant gene to diminish mutant SOD1 from muscle did not affect onset or survival. Finally, follistatin expression encoded by adeno-associated virus chronically inhibited myostatin and produced sustained increases in muscle mass, myofiber number, and fiber diameter, but these increases did not affect survival. Thus, SOD1-mutant-mediated damage within muscles is not a significant contributor to non-cell-autonomous pathogenesis in ALS, and enhancing muscle mass and strength provides no benefit in slowing disease onset or progression.siRNA ͉ adeno-associated virus ͉ motor neuron ͉ G93A SOD1 ͉ myostatin

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

“…It has been reported that muscle degeneration can cause denervation and some degenerative changes in motor neurons, including axon terminal degeneration and microgliosis in the spinal cord (71)(72)(73). However, most studies also demonstrate that muscle degeneration is not a primary driver for motor neuron death to the degree observed in ALS (71,72,74,75). Although one study suggested that mutant SOD1 expressed in muscles could drive motor neuron loss (73), the evidence was equivocal and inconsistent with the conclusions of other studies.…”

Activation of the Nrf2–ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1

“…Interestingly, the muscular ARE activation occurs most robustly in type I fibers, possibly because these fibers are more resistant to neuromuscular pathology. A recent study by Miller et al shows that specific knockdown of mutant SOD1 in the muscle alone has no effect on ALS pathology, whereas knockdown in the muscle and MNs together is sufficient to delay disease, suggesting that mutant SOD in the muscle is not a causative factor in ALS onset and progression [(Miller et al 2006)]. Taking these observations into consideration when evaluating our Nrf2-ARE activation in muscle leads us to hypothesize that early distal stress and muscle activation of the Nrf2-ARE pathway are independent of mutant SOD expression in muscle.…”

Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice

“…As to the identity of the cell types beyond motor neurons that contribute to disease onset, mutant synthesis within muscle has previously been shown not to affect either onset or progression (25). Mutant synthesis within microglia (8,9) or astrocytes (10) strongly accelerates disease progression, but expression in neither cell type seems to affect onset.…”