A study involving the SOD1 mouse may lead to a new therapy for amyotrophic lateral sclerosis (ALS) patients. In 2010, a research team based at the University of Rochester Medical Center showed that activated protein C (APC), a signaling protease with anticoagulant activity, slows disease progression and extends the life of an ALS mouse model, B6SJL-Tg(SOD1*G93A)1Gur/J (002726) (Zhong et al. 2009). The team found that, in this model, mutant SOD1 damages the microvessels that control the blood-spinal cord barrier (BSCB), allowing potentially neurotoxic blood components – such as hemoglobin and various reactive oxygen species – into the spinal cord. Permeation of the BSCB damages neuronal and non‑neuronal cells, including microglia and astrocytes. When APC is injected into the mouse, it crosses the BSCB via endothelial protein C receptor (EPCR) and affects the down-regulation of mutant SOD1 transcription in motor neurons and microglia. Reduced SOD1 levels prevent hemoglobin-derived products from leaking across the mouse's BSCB and inhibit disease progression.
Surprisingly, the team found that reducing SOD1 transcription in endothelial cells, which normally synthesize high levels of SOD1, does not impede disease progression, suggesting that neuronal-, microglia-, and astrocyte-synthesized mutant SOD1 are the major contributors to disease pathogenesis. The team also found that APC effectively reduces the expression of inflammatory markers and preserves innervation of the neuromuscular junctions in SOD1 mice for four weeks after disease onset, at which time untreated mice develop significant muscle weakness. SOD1 expression is reduced after APC signals to protease-activated receptor-1 (PAR1) and PAR3 to inhibit nuclear transport of the Sp1 transcription factor.
Researchers have become aware that APC protects against sepsis in humans, as well as in rodent models of Crohn's disease, diabetic nephropathy, stroke, tumor metastasis, multiple sclerosis and reperfusion injury (Esmon and Glass 2009). The findings by Zhong et al add ALS to this list. Although APC was originally known for its anticoagulant properties, its therapeutic effects in the mutant SOD1 mouse do not depend on those properties but depend rather on its enzymatic properties. However, if used as an ALS therapy, APC's anticoagulant properties may cause severe thrombotic complications. If those complications can be circumvented, APC may provide significant relief to the thousands of people afflicted with ALS.
Esmon C, Glass J. 2009. The APCs of neuroprotection. J Clin Invest. 119:3205–3208.
Zhong Z, Ilieva H, Hallagan L, Bell R, Singh I, Paquette N, Thiyagarajan M, Deane R, Fernandez JA, Lane S, Zlokovic AB, Liu T, Griffin JH, Chow N, Castellino FJ, Stojanovic K, Cleveland DW, Zlokovic BV. 2009. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest 119:3437–3449.