Too many fresh proteins at synapses might trigger neurodegeneration, Fernandes et al. reveal.

Synaptic vesicle–associated proteins help fill the vesicles with neurotransmitters, promote vesicle fusion, and perform other tasks necessary for synaptic transmission. But these proteins eventually wear out, so neurons continually steer the vesicles to endosomes, where the proteins are sorted. Functional proteins return to the synaptic vesicles to continue working, and the worn-out ones travel to the lysosome for destruction.

Fernandes et al. found that replacement of synaptic proteins was more efficent in flies with mutations in the gene skywalker, the insect homologue of TBC1D24, a human gene linked to neurodegeneration and epilepsy. The researchers tagged synaptic proteins with a fluorescent molecule that changes from blue to red over time, allowing them to determine the ages of the proteins. Young proteins were more abundant at synapses in the mutant flies than in controls. Synapses also were more active in mutant insects: they released larger quantities of neurotransmitters and triggered a larger postsynaptic electrical current after stimulation.

The researchers discovered that mutations in the gene encoding Dor counteract the effects of skywalker mutations, curtailing neurodegeneration, damping neurotransmitter release, and slowing synaptic protein turnover. Dor is part of the HOPS complex that helps direct endosomes to the lysosome for digestion. When HOPS is disabled, fewer old vesicle-associated proteins are lost from synapses.

The study suggests that aging is not always bad: without enough of these aged and less efficient vesicle-associated proteins, synapses become overactive and prompt neurodegeneration.

, et al
J. Cell Biol.

Author notes

Text by Mitch Leslie