Scientists have discovered a new genetic program in fruit flies that controls development of neurons and protects them from degeneration. The genes in this program have hardly changed over hundreds of millions of years of evolution and exist in comparable “homologous” forms in mammals, including humans. Initial results suggest these homologs might perform similar tasks in humans.
The findings are reported in the article, “Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed,” published in the journal Neuron. These new insights provide a starting point for the development of new therapeutics for neurodegenerative diseases.
Although the human brain is much larger and more complex than a fruit fly’s, there are molecular parallels between the two organisms. The current study discovers another.
“We specifically switched off individual genes and observed how the neurons changed as a result,” says Dietmar Schmucker, PhD, Humboldt Professor at the Life and Medical Sciences (LIMES) Institute at the University of Bonn and co-corresponding author on this study. “During this, we came upon a gene called WNK, which performs an incredible dual role.”
Schmucker and his team investigates genetic mechanisms responsible for the diversity and complexity of the brain by studying animal models such as the fruit fly (Drosophila melanogaster) and the western clawed frog, Xenopus tropicalis.
Azadeh Izadifar, PhD, a postdoctoral student in Schmucker’s group and lead author on the current study made the central discovery in the current study that WNK is necessary for connecting neurons during the development of the nervous system. Axons are cable-like neuronal extensions that transmit electrical signals by forming many synapses with other neurons. “Without the WNK protein, functional axonal branches are largely absent,” says Izadifar.
In adult animals WNK protects existing axons. If switched off in adults, the axonal branches already formed during developmental stages, degenerate.
“Both functions may be two sides of the same coin,” says Schmucker. WNK appears to be part of a regulatory network that controls both the formation of axonal branches during development and the degeneration of neural connections in adults.
WNK encodes a kinase–an enzyme that adds phosphate groups to other proteins to modify their fate or function. WNK regulates and supports a neuroprotective factor called Nmnat. WNK also inhibits at least two other axon-destabilizing proteins called Sarm and Axed that play an important role in the active neurodegeneration of axons. The researchers show excessive expression of Sarm or Axed causes defects in axon branching which can be blocked by increasing levels of WNK or Nmnat.
These results offer new impetus for understanding how neurodegenerative diseases occur in humans and how they could be treated.
As in fruit flies, WNK kinases exist in mammals where they also appear to be essential for protecting neurons, suggest experiments carried out in collaboration with a research group led by Franck Polleux, PhD, at Columbia University, New York. The team shows WNK kinases are important for the formation of axonal branches of neurons called pyramidal neurons in the cerebral cortices of mice and that their loss leads to the degeneration of their axons.
“It is also known that certain WNK mutations in humans lead to nerve damage, called peripheral neuropathy, which is accompanied by progressive sensory disorders in the arms and legs,” says Schmucker.
Schmucker hopes WNK kinase may be of therapeutic use in the fight against neurodegenerative diseases. For instance, its pharmacological overactivation may increase its ability to protect neurons.
The study was funded by the Belgian Research Foundation – Flanders, the Fondation pour la Recherche Medicale (FRM) in France, the European Union as part of its ERC Starting Grants, and by the Humboldt Foundation, the Roger De Spoelberch Fondation, and the Thompson Family Foundation Initiative. Scientists at the University of Bonn, KU Leuven, the Université de Lyon, Columbia University New York, and the University of Tokyo collaborated on this study.
