The authors discovered that mutations in a transcription factor found only in neurons increased aggregation of polyglutamine-containing proteins in muscle cells in C. elegans. This factor, UNC-30, boosts synthesis of GABA, which inhibits neuronal firing. Increased protein aggregation also resulted from other GABA-reducing (and thus neuronal stimulating) mutations, including one in the muscle cell's GABA receptor.
GABA's normal actions are counteracted by the stimulatory neurotransmitter acetylcholine. Mutation-induced overactivity of the acetylcholine system had the same effect on polyglutamine aggregation as too little GABA activity. Small molecules also had similar effects: nicotine, which stimulates neurons, promoted aggregation, as did an insecticide called lindane, which inhibits GABA.
“It is a stunning surprise that a transcription factor expressed only in the presynaptic cell can have such a profound effect on aggregation in the postsynaptic cell,” Morimoto says. The researchers are planning to seek evidence for similar effects in other communicating cells.
The polyglutamine protein used in these experiments contains just enough glutamines to be at the threshold of aggregation and is therefore exquisitely sensitive to outside influences. “Environment can play a big role in tipping the balance in such systems,” says Morimoto. The effects may help explain why polyglutamine diseases such as Huntington's arise at different times in siblings with identical repeat lengths.