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New insight into Huntington's disease pathology

Cell Press

The symptoms of Huntington's disease (HD)--severe loss of muscle control, emotional disturbance, and cognitive decline--are not just due to the toxic effects on brain cells of the mutant protein that causes the disorder, researchers, led by X. William Yang at Neuropsychiatric Institute of David Geffen School of Medicine at UCLA, have found. Their studies with genetically altered mice have revealed evidence for a new effect of the protein--triggering pathological interactions among brain cells.

The researchers said their findings could not only shed new light on the underlying causes of HD pathologies, but also those of other similar "polyglutamine repeat" (polyQ) diseases, in which mutant genes produce proteins with abnormally long strings of the amino acid glutamine. They said their findings also suggest that abnormal cell-cell interactions could also play a role in Alzheimer's and Parkinson's diseases.

In their studies, the researchers genetically engineered mice in which they could selectively trigger production of the mutant, toxic HD protein either throughout the brain or just in one restricted set of neurons. If only the toxic protein were required to produce the disease pathology, the "restricted-production" mice should show significant HD-type pathologies, reasoned the researchers. However, if abnormal interactions among cells throughout the brain were required for HD, these mice should show few or no pathologies compared to the engineered mice in which the mutant protein was produced in multiple neuron types throughout the brain.

Indeed, the researchers found that the mice that produced the toxic protein throughout their brains, but not those with restricted production, showed locomotor problems, neurodegeneration, abnormal electrophysiological connections, and HD-characteristic pathological processes in their brain tissue. The restricted-production mice showed little or no difference from normal mice in such measures of the disease pathology.

"This is the first direct genetic evidence to demonstrate that pathological cell-cell interaction can significantly contribute to the neuronal toxicity in vivo in a mouse model of HD," wrote Yang and his colleagues.

"Finally, our study has important implications for understanding the pathogenesis of other neurodegenerative disorders, including other polyQ disorders, familial Alzheimer's disease, and familial Parkinson's disease," they added. "All of these disorders are characterized by selective neurodegeneration caused by widely expressed disease proteins, but the molecular and cellular mechanisms underlying selective neurodegeneration in these disorders are poorly understood." For example, they wrote, mouse model studies of amyotrophic lateral sclerosis, or Lou Gehrig's disease, had shown that pathological cell-cell interactions are critical to motor degeneration. "Thus, pathological cell-cell interactions may be a surprisingly common pathogenic mechanism warranting further studies in all neurodegenerative disorders," they wrote.


The researchers include Xiaofeng Gu, Victor Lo, and X. William Yang of the Neuropsychiatric Institute; and Weizheng Wei, Istvan Mody of the Department of Neurology at David Geffen School of Medicine at UCLA; Chenjian Li of the Weill Medical College of Cornell University; Shiaoching Gong and Nathaniel Heintz of the Howard Hughes Medical Institute, Rockefeller University; Shi-Hua Li and Xiao-Jiang Li of Emory University School of Medicine; Takuji Iwasato of RIKEN Brain Science Institute and PRESTO, Japan Science and Technology Agency; and Shigeyoshi Itohara of RIKEN Brain Science Institute. The research and researchers were supported by grants from Hereditary Disease Foundation, Cisneros Children's Foundation, NIH/NINDS, and HHMI.

Gu, X., Li, C., Wei, W., Lo, V., Gong, S., Li, S.-H., Iwasato, T., Itohara, S., Li, X.-J., Mody, I., Heintz, N., and Yang, X.W. (2005). Pathological Cell-Cell Interactions Elicited by a Neuropathogenic Form of Mutant Huntingtin Contribute to Cortical Pathogenesis in HD Mice. Neuron 46, 433-444.

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