Scientist: Cell clean-up glitch may be Huntington's disease key

Scientists have shown that the breakdown of a key intracellular cleaning mechanism, caused by mutated huntingtin protein build up, may bring on the later, most devastating symptoms of Huntington's disease, a finding that suggests new treatment strategies.

Taking another step towards the discovery of an effective treatment for Huntington's disease, a team of scientists at Albert Einstein College of Medicine of Yeshiva University have shown that accumulating, mutated Huntingtin protein gums up a crucial cellular cleaning process, allowing more and more damaging toxic waste to build up in the cells of Huntington's disease patients. This damaging cellular behavior may be what brings on the condition's most severe symptoms, the scientists concluded. Senior author Ana Maria Cuervo, M.D., Ph.D., professor of medicine, of anatomy and structural biology and of developmental and molecular biology at Einstein explained:

"Studies have shown that Huntington's disease occurs in part because the mutated huntingtin protein accumulates within cells and is toxic to them. 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."

The team's research has been published in the April 11 online edition of Nature Neuroscience in a paper entitiled "Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease." According to background information provided by Albert Einstein College:

Huntington's disease, which famously afflicted the folksinger Woody Guthrie, is an inherited, neurodegenerative disorder that hits full-force during middle age, though less severe symtoms, such as diminishing physical skills and subtle personality changes, may begin appearing earlier.

Huntington's is caused by a dominant gene mutation (appearing in 50 percent of children of a parent with Huntington's) that leads to defective huntingtin protein formation in all an affected person's cells, so that the disease causes deterioration in the brain and every part of the body. Its more severe symptoms include uncontrollable jerky movements and dementia.

According to the paper, all cells rely on several different mechanisms to break down "old" proteins and other components and recycle them. Collectively known as autophagy (literally, "self-eating"), these processes keep cells clean and uncluttered and provide them with replacement parts that will function better. Earlier research by Cuervo and her team revealed that a glitch in the cellular breakdown and recycling of old components called autophagy ("self-eating") trigger Parkinson's disease symptoms by allowing a toxic protein to accumulate. Cuervo speculated that a similar malfuctioning process was happening in Huntington's disease. From observationing two mouse models of Huntington's disease and the activity of lymphoblasts (or white cells) from Huntington's patients, Cuervo and her team observed that the mutated huntingtin protein was short-circuiting clean-up and renewal efforts of cells. In the paper Cuervo detailed how mutated huntingtin protein blocks one essential mechanism of cellular clean-up, in which "garbage-bags" made of membrane, known as autophagosomes, form around old, used-up cellular structures and then fuse with enzyme-filled sacs, called lysosomes, that then digest their waste cargo. But in Huntington's disease, this clean-up mechansism breaks down when the defective huntingtin proteins stick onto the inner layers of autophagosomes and prevent them from picking up more of a cell's garbage, the scientists found. The researchers concluded that because the huntingtin proteins prevent the autophagosomes from functioning properly, these waste containers within the cells are empty when they travel to the lysosomes and merge with them for the "self-eating" process, so that intracellular toxic waste remains and builds up over time, contributing to cell damage and death. This new research indicates that a currently proposed treatment for Huntington's disease that aims to activate the lysosomes (where the contents of autophagosomes, the cell's garbage collectors, are broken down) will probably prove ineffective, Cuervo noted. "It doesn't matter how active your lysosomes are if they're not going to receive any cellular components to digest," she said. Cuervo suggested that Huntington's disease treatment research should focus instead on helping autophagosomes recognize and clear cellular debris. This project was initiated by initiated by Marta Martinez-Vicente, Ph.D., a postdoctoral fellow in Cuervo's lab. Esther Wong, Ph.D., a postdoctoral fellow with Cuervo, contributed to this research, along with Einstein researchers Esperanza Arias Ph.D., Susmita Kaushik Ph.D. and Hiroshi Koga, Ph.D., in collaboration with a team at Columbia University Medical School, led by Dr. David Sulzer. Digital Journalists reported earlier news about Huntington's Disease treatments and breakthroughs in February, 2010. The Huntington's Outreach Project for Education (HOPES) at Standford University has published additional background information on Huntington's disease.