Exogenous Delivery of Heat Shock Protein 70 Increases Lifespan in a Mouse Model of Amyotrophic Lateral Sclerosis

摘要

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder that results in the progressive loss of motoneurons (MNs) in the CNS. Several survival and death mechanisms of MNs have been characterized and it has been determined that MNs do not appear to mount a complete stress response, as determined by the lack of heat shock protein 70 (Hsp70) upregulation after several stress paradigms. Hsp70 has been shown to confer neuroprotection and the insufficient availability of Hsp70 may contribute to MNs' susceptibility to death in ALS mice. In this study, recombinant human Hsp70 (rhHsp70) was intraperitoneally injected three times weekly, beginning at postnatal day 50 until endstage, to G93A mutant SOD1 (G93A SOD1) mice. The administration of rhHsp70 was effective at increasing lifespan, delaying symptom onset, preserving motor function and prolonging MN survival. Interestingly, injected rhHsp70 localized to skeletal muscle and was not readily detected in the CNS. Treatment with rhHsp70 also resulted in an increased number of innervated neuromuscular junctions compared with control tissue. Together these results suggest rhHsp70 may delay disease progression in the G93A SOD1 mouse via a yet to be identified peripheral mechanism.