Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder in which motor neurons in the spinal cord and motor cortex degenerate. Although the majority of ALS cases are sporadic, mutations in Cu-Zn superoxide dismutase-1 (SOD1) are causative for 10-20% of familial ALS (fALS), and recent findings show that a hexanucleotide repeat expansion in the C9ORF72 gene may account for >30% of fALS cases in Europe. SOD1(G93A) transgenic mice have a phenotype and pathology similar to human ALS. In both ALS patients and SOD1(G93A) mice, the first pathological features of disease manifest at the neuromuscular junction, where significant denervation occurs prior to motor neuron degeneration. Strategies aimed at preventing or delaying denervation may therefore be of benefit in ALS. In this study, we show that Nogo-A levels increase in muscle fibres of SOD1(G93A) mice along with the elevation of markers of neuromuscular dysfunction (CHRNA1/MUSK). Symptomatic treatment of SOD1(G93A) mice from 70 days of age with an anti-Nogo-A antibody (GSK577548) significantly improves hindlimb muscle innervation at 90 days, a late symptomatic stage of disease, resulting in increased muscle force and motor unit survival and a significant increase in motor neuron survival. However, not all aspects of this improvement in anti-Nogo-A antibody-treated SOD1(G93A) mice were maintained at end-stage disease. These results show that treatment with anti-Nogo-A antibody significantly improves neuromuscular function in the SOD1(G93A) mouse model of ALS, at least during the earlier stages of disease and suggest that pharmacological inhibition of Nogo-A may be a disease-modifying approach in ALS.

Bros-Facer V ，Krull D ，Taylor A ，Dick JR ，Bates SA ，Cleveland MS ，Prinjha RK ，Greensmith L ... -  《-》

Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that, in the SOD1(G93A) rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1(G93A) rats through targeted delivery of AAV9-SOD1-shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.

Thomsen GM ，Gowing G ，Latter J ，Chen M ，Vit JP ，Staggenborg K ，Avalos P ，Alkaslasi M ，Ferraiuolo L ，Likhite S ，Kaspar BK ，Svendsen CN ... -  《-》

Amyloid precursor protein (APP) contributes to pathology in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

Bryson JB ，Hobbs C ，Parsons MJ ，Bosch KD ，Pandraud A ，Walsh FS ，Doherty P ，Greensmith L ... -  《-》

Progressive impairment of CaV1.1 function in the skeletal muscle of mice expressing a mutant type 1 Cu/Zn superoxide dismutase (G93A) linked to amyotrophic lateral sclerosis.

Beqollari D ，Romberg CF ，Dobrowolny G ，Martini M ，Voss AA ，Musarò A ，Bannister RA ... -  《Skeletal Muscle》

Microglia and motor neurons during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis: changes in arginase1 and inducible nitric oxide synthase.

Lewis KE ，Rasmussen AL ，Bennett W ，King A ，West AK ，Chung RS ，Chuah MI ... -  《Journal of Neuroinflammation》