The study demonstrates that muscle weakness experienced by persons with a regulatory protein tropomyosin mutation is directly related to a mechanism by which the mutant tropomyosin modulates contractile speed and force-generation capacity.
Dr. Julien Ochala and co-workers at the Department of Clinical Neurophysiology, University of Uppsala, in collaboration with scientists at the Department of Pathology, University of G?teborg, explored the mechanisms underlying the muscle weakness experienced by a woman and her daughter with a -tropomyosin mutation, i.e., muscle weakness in the absence of macro or microscopic signs of muscle wasting. The results from single fibre contractile measurements and in vitro motility analyses demonstrated a mechanism where tropomyosin modulates myosin-actin kinetics. A slower motor protein myosin attachment rate to and a faster detachment rate from actin, caused by the mutation, results in a reduced number of myosin molecules in the strong actin binding state and muscle weakness. The results also implicate a potential role of the regulatory protein tropomyosin in modulating contractile speed and force-generation under physiological conditions.
It is suggested that the findings at the gene, protein and muscle cell levels in this specific neuromuscular disorder will have a significant impact on our understanding of the disease pathogenesis and provide important information for future therapeutic strategies. Walter R. Frontera, an independent expert, says: "Dr. Ochala and collaborators have published elegant proof of the clinical consequences of mutations in the regulatory proteins of skeletal muscles. Their data provide strong support for the dissociation between qualitative alterations in muscle contractility and quantitative evidence of muscle atrophy".
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The Role of HDAC6 That's where the power of fruit flies comes in," Taylor explains. "We can use fruit flies to rapidly screen through many genes to find the one we"re interested in. In the process of screening, our attention was drawn to HDAC6 because we already knew that it could bind to ubiquitin-tagged proteins and transport them within the cell. So we wondered, could HDAC6 be the link""
Taylor's group showed that if the HDAC6 gene is knocked out, inducing autophagy no longer rescues the fly eyes from neurodegeneration. Therefore, autophagy requires HDAC6 to work. They also showed that by simply expressing extra HDAC6, neurodegeneration was prevented in flies with proteasome impairment. Taylor's group then moved on to fly models of human neurodegenerative disease and showed that they, too, are rescued by over-expression of HDAC6.
Therefore, the researchers suggest that the level of the HDAC6 in a cell regulates its sensitivity to accumulation of misfolded proteins, and that increasing the activity of HDAC6 can prevent the degeneration normally associated with accumulating old, damaged proteins. The researchers suggest further that when proteasomes are impaired or overwhelmed, which leads to accumulation of defective proteins, HDAC6 facilitates delivery to the autophagy-lysosomal system for degradation. "That's how we think HDAC6 links the two systems," says Taylor.
Dr Taylor and his team are now testing the ability of HDAC6 to prevent neurodegeneration in several mouse models, including motor neuron disease, Parkinson's disease, and Huntington's disease. They are also attempting to identify pharmacologic approaches to augmenting HDAC6 activity.
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