Administration of Recombinant Heat Shock Protein 70 Delays Peripheral Muscle Denervation in the SOD1G93AMouse Model of Amyotrophic Lateral Sclerosis

David J Gifondorwa,Crystal D Hayes,James Caress,Carol Milligan,Ramon Jimenz-Moreno,Hesam Rouhani,Jane L Strupe,Mac B Robinson

doi:10.1155/2012/170426

Abstract

A prominent clinical feature of ALS is muscle weakness due to dysfunction, denervation and degeneration of motoneurons (MNs). While MN degeneration is a late stage event in the ALS mouse model, muscle denervation occurs significantly earlier in the disease. Strategies to prevent this early denervation may improve quality of life by maintaining muscle control and slowing disease progression. The precise cause of MN dysfunction and denervation is not known, but several mechanisms have been proposed that involve potentially toxic intra- and extracellular changes. Many cells confront these changes by mounting a stress response that includes increased expression of heat shock protein 70 (Hsp70). MNs do not upregulate Hsp70, and this may result in a potentially increased vulnerability. We previously reported that recombinant human hsp70 (rhHsp70) injections delayed symptom onset and increased lifespan in SOD1G93A mice. The exogenous rhHsp70 was localized to the muscle and not to spinal cord or brain suggesting it modulates peripheral pathophysiology. In the current study, we focused on earlier administration of Hsp70 and its effect on initial muscle denervation. Injections of the protein appeared to arrest denervation with preserved large myelinated peripheral axons, and reduced glial activation.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motoneurons (MNs), resulting in gradual muscle weakening and loss of MN function leading to paralysis and death of afflicted individuals
While we did not perform behavioral analysis in this study, we found that administration of recombinant human hsp70 (rhHsp70) substantially delays early muscle denervation such that the level of muscle innervation present at the start of treatment (P30) was maintained for 1.5 months in treated animals whereas it significantly decreased in untreated mice over this same period
While the amounts of rhHsp70 in MNs may be below the level of detection, an alternative hypothesis is that the administered protein is acting via an extracellular mechanism at the neuromuscular junction (NMJ)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motoneurons (MNs), resulting in gradual muscle weakening and loss of MN function leading to paralysis and death of afflicted individuals. The death of MNs occurs late in the disease process in mouse models, and even when physical degeneration of the cell is prevented, survival of the animal is only moderately prolonged [1]. Clinical onset of behavioral pathology is generally considered to occur during the third postnatal month; we, and others have observed more subtle behavior changes at earlier time points ([6]; unpublished observations). Pathological events such as fragmentation of the Golgi apparatus, vacuolization of mitochondria, deficits in axonal

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Conclusion