In a roundworm, the same neuronal receptor protects against the Alzheimer’s protein by breaking up its aggregates and against the Huntington’s protein by assembling larger aggregates
In a roundworm, the same neuronal receptor protects against the Alzheimer’s protein by breaking up its aggregates and against the Huntington’s protein by assembling larger aggregates
On October 9, Ehud Cohen’s laboratory at the Hebrew University of Jerusalem published a study in Science Advances answering a question it had raised thirteen years earlier: why gtr-1, a gene encoding a receptor on the surface of neurons in the roundworm Caenorhabditis elegans, can either protect or harm the animal in models of Alzheimer’s and Huntington’s diseases.
In 2013, the same laboratory found something puzzling: worms without gtr-1 were less tolerant of heat, yet silencing the same gene protected them from amyloid beta, an aggregation-prone protein that accumulates in the brain in Alzheimer’s disease. The same gene could be harmful or protective, depending on the threat. The new paper explains how this is possible.
The team tested a second model: worms with long, aggregation-prone glutamine chains of the kind that cause Huntington’s disease in humans. Silencing gtr-1 also protected these worms, but through the opposite mechanism: the Alzheimer’s protein was broken down into small, harmless pieces, while the Huntington’s protein assembled into large aggregates, which rendered it harmless. Toxicity comes from small, mobile protein aggregates. The body can therefore protect itself either by removing the protein from circulation or by sequestering it in a large, immobile aggregate.
The two responses also depend on different molecular switches: protection against amyloid beta requires SKN-1, a protein that senses toxic substances in the cell, while protection against the Huntington’s protein requires DAF-16, one of the main regulators of aging in roundworms. Cohen first linked these two switches to protection against protein aggregation twenty years ago, in a 2006 Science paper led by Andrew Dillin. Since then, his own laboratory has been investigating what activates these switches at the right time. Disabling the switch required for a particular response eliminates protection entirely.
Neuropeptides carry the signal from neurons to muscles. These short signaling molecules allow nerve cells to communicate with the rest of the body. Under the threat of amyloid beta, gtr-1 knockdown changes the activity of 388 genes across the worm’s body; under the threat of the Huntington’s protein, it changes the activity of 1213, more than three times as many. Of four neuropeptides involved in protection, one, nlp-59, has opposite requirements in the two disease models: it is dispensable for protection against amyloid beta but essential for protection against the Huntington’s protein. The nervous system identifies which protein threatens the body and sends the appropriate set of signals.
The tissues increase the activity of two mechanisms for clearing protein waste: the proteasome, a molecular machine that breaks down proteins, and autophagy, which packages them into vesicles for digestion. Chemically blocking the proteasome completely eliminates protection against the Huntington’s protein, even while gtr-1 remains suppressed.
The authors acknowledge that part of the picture remains unresolved:
How neurons coordinate protein protection throughout the organism remains only partly understood.
A key step remains unexplained: how a neuron identifies the protein threatening the body. The authors propose two hypotheses: the signal may pass through glial cells or through the intestine. Neither possibility was tested in this study.
The authors of the paper suggest a potential future medical application:
Administering a specifically selected combination of neuropeptides, and possibly other signaling molecules, could delay or perhaps even prevent the onset of late-onset neurodegenerative diseases.