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New drug target raises hopes for Alzheimer’s and ALS treatment


A new study shows that inhibiting a key enzyme may stop neurodegenerative diseases in their tracks.


Composite MRI/CT scan of a skull showing the brain.
Degenerative diseases of the brain are very difficult to treat.
Zephyr / Science Photo Library

Finding a successful treatment for Alzheimer’s disease has for decades seemed like an impossible feat, but a new discovery may change that – and treat other neurodegenerative diseases, too.

A research team led by Claire Le Pichon of venerable US biotech firm Genentech, and including scientists from universities in San Francisco and Hamburg, has identified a single protein to target for the treatment of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and potentially other degenerative conditions of the brain.

The team report in a paper published in Science Translational Medicine that, using mouse models of both diseases , they investigated whether a particular type of stress response was linked to the diseases.

Known as the DLK/JNK signalling pathway, it involves two partner enzymes (JNK (c-Jun N-terminal kinase) and DLK (dual leucine zipper kinase)). It was already known to respond to stressed brain cells in one of two ways: rescue or death. The challenge was to tweak the pathway to push it rescue.

So far, researchers had tried targeting the activity of the JNK enzyme, but failed to push the pathway towards rescue. This time around Le Pichon and colleagues went after its partner, DLK. They met with success. Chemicals that inhibited DLK decreased the stress-signalling activity. The AD mice had boosted neuron and synaptic survival, and neuron degeneration diminished in both diseased and non-diseased models. Most importantly, it also meant that the ALS mice lived longer and had better cognitive function,

The work is very significant for two main reasons, says neuroscientist Bryce Vissel at the University of Technology, Sydney, who was not involved in the research.

“First, they’ve found not only a new target for treatment, but an actual drug that can be tested. And second, this shows that pharmaceutical companies are investigating new ways forward for the treatment of Alzheimer’s [and other neurodegenerative disease]. Everyone else is researching amyloid beta and tau [toxic protein deposits that have been the major targets for drug developers], but Genentech has come up with something new.”

Genentech has started work on a Phase I clinical trial of a medication designed to block DLK, for potential ALS treatment.

“The medication may have side effects, issues with clinical safety,” says Vissel. “This may be another great white hope that disappears into the distance. But that doesn’t detract from the significance of the discoveries.”

Ariella Heffernan-Marks in a Melbourne-based science writer.
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