%0 Journal Article
%T Administration of Recombinant Heat Shock Protein 70 Delays Peripheral Muscle Denervation in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis
%A David J. Gifondorwa
%A Ramon Jimenz-Moreno
%A Crystal D. Hayes
%A Hesam Rouhani
%A Mac B. Robinson
%A Jane L. Strupe
%A James Caress
%A Carol Milligan
%J Neurology Research International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/170426
%X 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. 1. 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 ultimately leading to paralysis and death of afflicted individuals. Much ALS research has focused on MN cell bodies and dendrites within the spinal cord and the role of local glial cells. Many therapeutic interventions have been designed to intervene in pathological events that occur in the anterior horn region with the goal of preventing MN cell body degeneration. However, 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]. More recently, research has focused attention on early events including muscle denervation that begins during the first postnatal month in the mouse [1¨C5]. Clinical onset of behavioral pathology is generally considered to occur during the third postnatal month; however, we, and others have observed more subtle behavior changes at earlier time points ([6]; unpublished observations). Furthermore, pathological events such as fragmentation of the Golgi apparatus, vacuolization of mitochondria, deficits in axonal transport,
%U http://www.hindawi.com/journals/nri/2012/170426/