In lab cells and mice, neurons unlock a hidden defense against ALS

A protein that should stay in the nucleus of a neuron is slipping into the cytoplasm, where it clumps and starves the cell of its function. That is the situation the Nagoya University team reproduced in human neuron cultures and in mice. Their finding, published in EMBO reports, is that the neuron does not simply watch it happen: it fights back, through a machine it was not thought to use. The protein is TDP-43, and in most cases of ALS (amyotrophic lateral sclerosis, a disease that destroys motor control) it is the one that aggregates.

The starting point is a puzzle. TDP-43 normally operates in pairs or small groups inside the nucleus. Under sudden stress, the team showed, it stops forming these groups, and is then re-exported to the cytoplasm as what Koji Yamanaka calls "some form of dysfunctional waste". Healthy cells usually clear such waste, but the mechanism had not been well understood. The usual suspect was autophagy, the process that gathers faulty proteins into small vesicles and digests them. Shohei Sakai, a project assistant professor who joined the lab as a graduate student, tested that idea directly: inhibiting autophagy did not stop the removal of TDP-43.

The answer lies in a second signal. The sensor molecule TBK1, which physically binds the exported TDP-43, also activates a signal molecule called interferon beta. That signal can be perceived by neighbouring cells, and where it arrives, neurons increase production of the immunoproteasome, a protein-digesting machine that cells normally make in immune cells during viral infections. The immunoproteasome breaks TDP-43 into fragments before it can aggregate. The team also found that in spinal cord samples from ALS patients, the receptor for this signal was present in significantly lower quantities than in people without the disease.

For patients, the immediate change is a new target rather than a new drug. The pathway offers, in the team's words, "a new potential path to developing a treatment", but the team is clear about its limits. Interferon beta is already used for other conditions, and its severe side effects, because it triggers many reactions, mean it does not seem to be a practical option for ALS. The next project aims to find other compounds that can activate the immunoproteasome in motor neurons. The researchers say they still need to establish the real therapeutic potential of the pathway, and no timeline for that work has been given. What the study does establish is that motor neurons possess a defense against this protein that medicine had not counted on.