"Sticky" Mice Lead to Discovery of New Cause of Neurodegenerative Disease
JAX® NOTES Issue 503, Fall 2006
Howard Hughes Medical Institute investigator Dr. Susan L. Ackerman and her colleagues at The Jackson Laboratory, and collaborators at The Scripps Research Institute, recently discovered a novel mechanism responsible for the accumulation of a toxic sludge of misfolded proteins that kills neurons. Such sludge build-ups are characteristic of Alzheimer's and Huntington's diseases.
The researchers made their discovery by studying a mouse with a mutation called sticky (sti). Named for the sticky appearance of its fur, the sticky mouse has a much more serious problem: poor muscle control (ataxia) due to death of Purkinje cells in the cerebellum. The team found that a subtle defect in a gene that encodes alanyl tRNA synthetase, an enzyme that plays an important role in protein synthesis, is responsible. The enzyme is supposed to load the amino acid alanine onto transfer RNAs (tRNAs), which then transport the alanine to ribosomes, where it is added to proteins under construction. Instead, the sticky mouse's defective enzyme loads a similar amino acid, serine, which results in misfolded proteins. The effect of the defective enzyme was verified when sticky mice genetically engineered to harbor the normal gene were disease free.
The investigators were surprised at their discovery because they thought that an organism with such a fundamental defect could not survive. Says Ackerman: "Our finding that this mechanism underlies a neurodegenerative disease was highly unexpected. It was perfectly obvious that mischarged tRNAs may generate misfolded proteins. But what surprised us was that such a small increase in mischarged tRNAs could have such a devastating result in terms of neuronal survival. Nobody I know of has put forth such a mechanism for human neurological disease." She speculates that some human neurorological diseases may arise when a mild inherited defect in a tRNA synthetase causes a subtle increase in malformed proteins, killing particularly vulnerable cells such as Purkinje cells.
Dr. Ackerman and her colleagues are conducting further studies to understand why Purkinje cells are vulnerable to defects in protein synthesis. They are also exploring how the actions of other genes can alleviate the pathology caused by protein misfolding.
Reference
Lee JW, Beebe K, Nangle LA, Jang J, Longo-Guess CM, Cook SA, Davisson MT, Sundberg JP, Schimmel P, Ackerman SL. 2006. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature Aug 13; [Epub ahead of print].
This article was modified from a press release by the Howard Hughes Medical Institute, 8/13/06.
