An Ionic Sensor acts in Parallel to dSarm to Promote Neurodegeneration

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Mechanisms by which neurons detect terminal dysfunction and initiate neurodegeneration are not fully understood.
• The NAD+-dependent hydrolase SARM1 (in mammals) or dSarm (in Drosophila) acts as a metabolic sensor, triggering axon degeneration.
• SARM1/dSarm detects altered NAD+/NMN ratios, leading to catastrophic axon degeneration.

Purpose of the Study:

• To investigate novel pathways involved in neuronal dysfunction and neurodegeneration.
• To identify additional sensors beyond SARM1/dSarm that contribute to neurodegeneration.
• To elucidate the signaling cascade leading to axon degeneration and neuronal cell death.

Main Methods:

• Utilized Drosophila melanogaster as a model organism.
• Investigated the role of Drosophila with-no-lysine kinase (dWnk) in neurodegeneration.
• Examined the interaction between dWnk, dSarm, Frayed, and Axundead (Axed) in neurodegenerative pathways.

Main Results:

• Drosophila dWnk directly senses chloride (Cl-), potassium (K+), and osmotic pressure.
• dWnk is essential for neurodegeneration induced by the depletion of NAD+ biosynthetic enzyme dNmnat.
• dWnk functions in parallel to dSarm, promoting axon degeneration and neuronal death via the kinase Frayed and converging on Axundead (Axed).

Conclusions:

• Neurons employ distinct sensors for metabolic status (dSarm/SARM1) and ionic/osmotic conditions (dWnk) to assess cellular health.
• Dysfunctional neurons activate neurodegeneration through parallel pathways involving dWnk and dSarm.
• Both pathways converge on the molecule Axundead (Axed) to execute the process of neurodegeneration.