LAUSR

Axonal loss occurs in many neurologic disorders and its prevention is a major target of disease-modifying therapies. Over the past several years, studies in the Wlds mutant mouse model characterized by delayed Wallerian degeneration (WD) following axonal transection have provided important insights into the mechanisms of axon death.1-3 Wlds mutant mouse axons survive 10-fold longer than in wild-type mice following axotomy. Studies show that WD occurs via a canonical pathway that results in a reduced availability of nicotinamide adenine dinucleotide (NAD+) and thus directly affects energy metabolism.4-6 Accordingly, there is increasing evidence that mitochondria have a critical role as initiators of the axonal degeneration program.7,8 Axons are particularly vulnerable to mitochondrial damage given their high energy requirement.9 The basic pathways for axon injury are relevant not only following transection, but also in a wide range of axonal disorders, as supported by several preclinical disease models4-6 (Figure). The effects of mutations in genes regulating the axonal injury program in humans10-15 confirm that these basic mechanisms occur in a wide range of neurologic disorders. The elucidation of the central regulators of programmed axon death4,5,16-20 and the identification of molecular biomarkers that signal the activation of this process21 provide potential therapeutic targets for axonal protection.22