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Neurons have more extended and complex shapes than other cells and consequently face a greater challenge in distributing and maintaining mitochondria throughout their arbors. Neurons can last a lifetime, but proteins turn over rapidly. Mitochondria, therefore, need constant rejuvenation no matter how far they are from the soma. Axonal transport of mitochondria and mitochondrial fission and fusion contribute to this rejuvenation, but local protein synthesis is also likely. Maintenance of a healthy mitochondrial population also requires the clearance of damaged proteins and organelles. This involves degradation of individual proteins, sequestration in mitochondria-derived vesicles, organelle degradation by mitophagy and macroautophagy, and in some cases transfer to glial cells. Both long-range transport and local processing are thus at work in achieving neuronal mitostasis—the maintenance of an appropriately distributed pool of healthy mitochondria for the duration of a neuron’s life. Accordingly, defects in the processes that support mitostasis are significant contributors to neurodegenerative disorders.

Paclitaxel is a microtubule-binding compound that is widely used as a chemotherapeutic in the treatment of common cancers, including breast and ovarian cancer. Paclitaxel binding along the length of microtubules stabilizes them and suppresses their dynamics, leading to mitotic arrest and apoptosis in dividing cells. Though they are not dividing cells, neurons are also susceptible to paclitaxel, and paclitaxel exposure results in axonal degeneration. Thus a frequent side effect of paclitaxel treatment in patients is peripheral neuropathy, which can necessitate dose reductions and have lasting symptoms. An understanding of the mechanisms underlying paclitaxel s neurotoxicity is important for development of therapeutics to prevent and alleviate the neuropathy. Here we will review approaches taken to investigate mechanisms of paclitaxel-induced neuropathy and evidence for potential mechanisms of the axonal degeneration downstream of or distinct from microtubule stabilization by paclitaxel. This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.

Neurons, perhaps more than any other cell type, depend on mitochondrial trafficking for their survival. Recent studies have elucidated a motor/adaptor complex on the mitochondrial surface that is shared between neurons and other animal cells. In addition to kinesin and dynein, this complex contains the proteins Miro (also called RhoT1/2) and milton (also called TRAK1/2) and is responsible for much, although not necessarily all, mitochondrial movement. Elucidation of the complex has permitted inroads for understanding how this movement is regulated by a variety of intracellular signals, although many mysteries remain. Regulating mitochondrial movement can match energy demand to energy supply throughout the extraordinary architecture of these cells and can control the clearance and replenishing of mitochondria in the periphery. Because the extended axons of neurons contain uniformly polarized microtubules, they have been useful for studying mitochondrial motility in conjunction with biochemical assays in many cell types.

In this issue of Neuron, work from Moughamian and Holzbaur (2012) and Lloyd et al. (2012) reveals a role for p150 in initiation of retrograde transport at synaptic terminals. These studies also suggest how mutations of p150 s CAP-Gly domain lead to both Perry syndrome and HMN7B disease.

Tight control of synapse formation ensures that neurons connect to appropriate targets. In this issue of Neuron, Klassen et al. identify ARL-8 GTPase as a regulator of presynaptic assembly. Without ARL-8, presynaptic material aggregates en route to its destination, suggesting that ARL-8 acts like a dispersant to prevent premature synaptic assembly in the axon.