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'Sticky' mice lead to discovery of new cause of neurodegenerative disease

When a faulty protein wreaks havoc in cells and causes disease, researchers are usually quick to point the finger at a wayward gene. Now scientists are learning that some neurodegenerative diseases can develop even though a gene is perfectly normal. The diseases can be caused when the genetic instructions contained in the gene are not executed properly, leading to a lethal buildup of malformed proteins in brain cells.

The new studies by Howard Hughes Medical Institute (HHMI) investigator Susan L. Ackerman and colleagues at The Jackson Laboratory point to a novel mechanism behind the buildup of the toxic sludge that accumulates in neurons. Researchers have long known that neurodegenerative disorders can be caused by the gradual yet persistent accumulation of misfolded proteins in neurons that eventually triggers cell death. But this new mechanism points to errors in executing the genetic instructions, which are distinct from known causes of neurodegenerative diseases, such as Alzheimer's and Huntington's diseases.

HHMI investigator Susan L. Ackerman and her colleagues reported their findings in an August 13, 2006, advance online publication of the journal Nature. Ackerman's group collaborated on the studies with co-author Paul Schimmel at The Scripps Research Institute.

The researchers made their discovery by studying mice with a mutation called sticky (sti). Although named for the sticky appearance of their fur, the mice harbor much more serious problems beneath their unkempt coats: poor muscle control, or ataxia, due to death of Purkinje cells in a region of the brain called the cerebellum.

No one knew why Purkinje cells were dying in sticky mutant mice. To find out, Ackerman and her colleagues searched for the gene that was disrupted by the sti mutation. They were surprised to find a subtle defect in a gene that codes for part of the cell's protein synthesis machinery -- an enzyme called alanyl
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Source:Howard Hughes Medical Institute


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