How axons survive for as long as we live: an integrated view at axon biology and pathology.

Axons are up-to-meter long neuronal processes that form the biological cables wiring nervous systems. In humans these delicate structures can survive for a century. Their extreme anatomy and longevity require a high degree of self-sufficiency. Key roles are played by the axonal cytoskeleton contributing to virtually all biological processes that sustain axons. Studying over 50 actin- and microtubule (MT)-regulators in Drosophila neurons and incorporating the wider literature, we developed the "dependency cycle of local axon homeostasis" as a promising new concept explaining long-term maintenance of axons and their pathologies. In a nutshell: (1) axonal transport is essential for axon function and physiology; (2) MT bundles provide the essential highways for axonal transport; (3) axonal transport imposes mechanical stress that damages MT bundles; (4) consequently, MT bundles are actively maintained by MT-binding proteins; (5) this maintenance depends on materials, components and physiology supplied by transport - thus closing the dependency cycle (see animated summary: https://poppi62.wordpress.com/dclah). Breaking the dependency cycle in any position leads to bundle decay and can explain why trauma, intoxication, various genetic defects or ageing can cause very similar pathologies. Here I will present the molecular mechanisms contributing to the dependency cycle that we have uncovered so far.