When Ackerman and her colleagues examined the Purkinje cells of sticky mouse mutants, this is exactly what they saw. They also detected biochemical evidence that the cells were making an unsuccessful effort to tag and destroy the accumulating misfolded proteins.
"Our finding that this mechanism underlies a neurodegenerative disease was highly unexpected," said Ackerman. "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."
Ackerman speculates that human disease could arise when a mild inherited defect in a tRNA synthetase led to a subtle increase in malformed proteins, which could cause the death of particularly vulnerable cells such as Purkinje cells. "This mouse model shows that such a mechanism is possible," she said. "The sticky mouse has a mild editing defect that still allows it to produce offspring.
"So, a major question to be explored in human populations is whether the subtle loss of translational fidelity from such a defect could lead to various human diseases ?particularly those that involve the accumulation of misfolded proteins," she said.
Ackerman and her colleagues are conducting further studies to understand why Purkinje cells are particularly vulnerable to defects in
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Source:Howard Hughes Medical Institute