亨廷顿舞蹈病可能由蛋白质突变导致

In a step towards a possible treatment for Huntington's disease, scientists at Albert Einstein College of Medicine of Yeshiva University have shown for the first time that the accumulation of a mutated（变化，突变） protein may explain damaging cellular¹ behavior in Huntington's disease. Their research is described in the April 11 online edition of Nature Neuroscience. Huntington's disease, which afflicted²（折磨，使痛苦） the folksinger Woody Guthrie, is a fatal, inherited neurodegenerative（神经变性的） disorder⁴. While subtle personality changes and diminished（减退的） physical skills may occur early in the disease, it typically becomes noticeable during middle age. Later problems include dementia（痴呆） and chorea（舞蹈病） – jerky movements that are random⁵ and uncontrollable.

Huntington's disease results from a gene³ mutation⁶ that leads to a defective⁷ form of the huntingtin（变异亨廷顿蛋白） protein. The mutation is dominant⁸（支配的，统治的） , meaning that a child of an affected⁹ parent has a 50 percent chance of inheriting Huntington's. And since the defective protein is present in all of a person's cells, the disease causes problems in the brain and throughout the body.

"Studies have shown that Huntington's disease occurs in part because the mutated huntingtin protein accumulates within cells and is toxic¹⁰ to them," said Ana Maria Cuervo, M.D., Ph.D., professor of developmental and molecular¹¹ biology, of anatomy¹² and structural¹³ biology, and of medicine at Einstein and senior author of the Nature Neuroscience study. "In our investigation¹⁴ of how the accumulating huntingtin protein affects the functioning of cells, we found that it interferes¹⁵ with the cells' ability to digest and recycle their contents."

All cells rely on several different mechanisms¹⁷ to break down "old" proteins and other components¹⁸ and recycle them. Collectively known as autophagy（自我吞噬） (literally, "self-eating"), these processes keep cells clean and uncluttered（整洁的，整齐的） and provide them with replacement¹⁹ parts that will function better.

Dr. Cuervo and her team had previously²⁰ shown that a glitch²¹（小故障，失灵） in autophagy may trigger Parkinson's disease by allowing a toxic protein to accumulate. She suspected that something similar was going on in Huntington's disease. After studying two mouse models of Huntington's disease as well as lymphoblasts (white cells) from people with the disease, she and her team found that the mutated huntingtin protein was sabotaging²²（妨害，破坏） the cell's garbage-collecting efforts.

One mechanism¹⁶ for cleaning up cells involves forming a membrane²³ around the protein or other cellular structure requiring removal. These "garbage bags" (more formally known as autophagosomes) then travel to enzyme-filled sacs known as lysosomes（溶酶体） that fuse with（融合，联合） the bags and digest their cargo²⁴. But the clean-up efforts go awry²⁵ in Huntington's disease.

Dr. Cuervo and her team found that the defective huntingtin proteins stick to the inner layer of autophagosomes, preventing them from gathering²⁶ garbage. The result: Autophagosomes arrive empty at the lysosomes; and cellular components that should be recycled instead accumulate, causing toxicity²⁷ that probably contributes to cell death.

This finding, Dr. Cuervo noted²⁸, shows that activating²⁹ the lysosomes of cells – one of the proposed treatments for Huntington's disease – won't do any good.

"It doesn't matter how active your lysosomes are if they're not going to receive any cellular components to digest," she said. "Instead, we should focus on treatments to help autophagosomes recognize intracellular（细胞内的） garbage, perhaps by minimizing their contact with the defective huntingtin protein. By enhancing the clearance³⁰ of cellular debris³¹, we may be able to keep Huntington's patients free of symptoms（症状） for a longer time."