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Penn researchers link cell's protein recycling systems

ation always got worse,” says Taylor. “Then when we activated the autophagy system by feeding the flies a drug called rapamycin, neurodegeneration was prevented.” The accumulated misfolded proteins were cleared out by the lysosome system. “Then we knew that this system can compensate for the impaired proteasome function, which in itself tells us that the two pathways intersect,” says Taylor. “The question was, ‘How is this working"’”

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 moto
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Source:University of Pennsylvania School of Medicine


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