Faulty cleanup process could be key to Huntington's

Scientists at Albert Einstein College of Medicine of Yeshiva University have shown that the accumulation of a mutated protein may explain damaging cellular behavior in Huntington's disease, a condition resulting from a gene mutation that leads to a defective form of the huntingtin protein.

"Studies have shown that Huntington's disease occurs in part because the mutated huntingtin protein accumulates within cells," says senior author Ana Maria Cuervo. "In our investigation of how the accumulating huntingtin protein affects the functioning of cells, we found that it interferes with the cells' ability to digest and recycle their contents."

Cells rely on different mechanisms to break down old proteins and other components and recycle them through processes known collectively as authophagy. These processes keep cells clean and provide them with replacement parts. Cuervo's team had previously shown that a glitch in autophagy may trigger Parkinson's disease, and she suspected that something similar was going on in Huntington's patients. After studying two mouse models, as well as lymphoblasts from people with the disease, she and her team found that the mutated huntingtin protein was sabotaging the cell's cleaning efforts.

One mechanism for cleaning up cells involves forming a membrane around the protein or other cellular structure requiring removal. These autophagosomes then travel to enzyme-filled sacs known as lysosomes that fuse with the bags and digest their cargo.  Cuervo and her team found that the defective huntingtin proteins stick to the inner layer of autophagosomes, preventing them from gathering garbage. The result: Autophagosomes arrive empty at the lysosomes; and cellular components that should be recycled instead accumulate, causing toxicity that probably contributes to cell death.

This finding shows that activating the lysosomes of cells--one of the proposed treatments for Huntington's disease--won't do any good, Cuervo says. Her team's paper appears in the April 11 online issue of Nature Neuroscience.

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