How do axons degenerate?

Axon degeneration (AxD) is a hallmark in neurodegenerative diseases, metabolic abnormalities, chemotherapy, and traumatic brain injury. Despite its prevalence, we know very little about the genetic program that drives AxD. A growing list of studies shows that absence of Sarm1, a conserved pro-degenerative molecule, protects axons from degeneration in disease models. Interestingly, mutations hyperactivating Sarm1 were also found in patients suffering from ALS and other motor neurons disorders. Despite its key role in neurodegeneration, we do not understand how Sarm1 is activated and whether independent pathways parallel to Sarm1 exist. To address these questions, we performed an unbiased F1 forward genetic screen, in which we activated dSarm and induced AxD by knocking down Nmnat. A pilot screen of 6,000 chromosomes allowed us to isolate new molecules mediating AxD, including dWnk (With-no-Lysine) kinase. Wnk kinases are unique in their ability to sense intracellular concentrations of chloride ([Cl^-]_i). They phosphorylate and activate downstream kinases (e.g. Frayed/STK39) to regulate the activity of cation-chloride cotransporters that mobilize [Cl^-]_i. Our preliminary data suggest that both dWnk and Frayed promote AxD, and are activated in parallel to dSarm upon Nmnat depletion. We are currently investigating the mechanism by which dWnk activates AxD, and where dWnk sits in AxD genetic pathways.