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Synaptic defects associated with s-inclusion body myositis are prevented by copper

Abstract

Sporadic-inclusion body myositis (s-IBM) is the most common skeletal muscle disorder to afflict the elderly, and is clinically characterized by skeletal muscle degeneration. Its progressive course leads to muscle weakness and wasting, resulting in severe disability. The exact pathogenesis of this disease is unknown and no effective treatment has yet been found. An intriguing aspect of s-IBM is that it shares several molecular abnormalities with Alzheimer’s disease, including the accumulation of amyloid-β-peptide (Aβ). Both disorders affect homeostasis of the cytotoxic fragment Aβ1-42 during aging, but they are clinically distinct diseases. The use of animals that mimic some characteristics of a disease has become important in the search to elucidate the molecular mechanisms underlying the pathogenesis. With the aim of analyzing Aβ-induced pathology and evaluating the consequences of modulating Aβ aggregation, we used Caenorhabditis elegans that express the Aβ human peptide in muscle cells as a model of s-IBM. Previous studies indicate that copper treatment increases the number and size of amyloid deposits in muscle cells, and is able to ameliorate the motility impairments in Aβ transgenic C. elegans. Our recent studies show that neuromuscular synaptic transmission is defective in animals that express the Aβ-peptide and suggest a specific defect at the nicotine acetylcholine receptors level. Biochemical analyses show that copper treatment increases the number of amyloid deposits but decreases Aβ-oligomers. Copper treatment improves motility, synaptic structure and function. Our results suggest that Aβ-oligomers are the toxic Aβ species that trigger neuromuscular junction dysfunction.

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Acknowledgments

We thank Paula Grez, for her contribution to Fig. 1 of this work, and Dr. William Klunk for providing the X-34 dye. We are grateful to Dr. Chris Link for his generous gift of C. elegans strains. Some strains were provided by the Caenorhabditis Genetics Center (CGC). Financial support: Grant 13980001, Centro de Envejecimiento y Regeneración (CARE), Programa de Financiamiento Basal 12/2007. FONDECYT 1120213 to RA.

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Correspondence to R. Aldunate.

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R. Aldunate and A. N. Minniti contributed equally to this study.

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Aldunate, R., Minniti, A.N., Rebolledo, D. et al. Synaptic defects associated with s-inclusion body myositis are prevented by copper. Biometals 25, 815–824 (2012). https://doi.org/10.1007/s10534-012-9553-7

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Keywords

  • Inclusion body myositis
  • Amyloid-β-peptide
  • Copper
  • C. elegans
  • Neuromuscular junction