Retrograde axonal transport: pathways to cell death?

Abstract

Active transport along the axon is critical to the neuron. Motor-driven transport supplies the distal synapse with newly synthesized proteins and lipids, and clears damaged or misfolded proteins. Microtubule motors also drive long-distance signaling along the axon via signaling endosomes. While positive signaling initiated by neurotrophic factors has been well-studied, recent research has focused on stress signaling along the axon. Here, the connections between axonal transport alterations and neurodegeneration are discussed, including evidence for defective transport of vesicles, mitochondria, degradative organelles, and signaling endosomes in models of Amyotrophic Lateral Sclerosis, Huntington's, Parkinson's and Alzheimer's disease. Defects in transport are sufficient to induce neurodegeneration, but recent progress suggests that changes in retrograde signaling pathways correlate with rapidly progressive neuronal cell death. Active axonal transport maintains extended neuronal processesThe unique morphology of neurons, highly polarized cells with extended axons and dendrites, makes them particularly dependent on active intracellular transport. The transport of proteins, RNA, and organelles over long distances requires molecular motors that operate along the cellular cytoskeleton (Glossary).Two major roles for axonal transport are supply/clearance and long-distance signaling. Supply of newly synthesized proteins and lipids to the distal synapse maintains axonal activity, while misfolded and aggregated proteins are cleared from the axon by transport to the cell soma for efficient degradation [1]. Active transport of mitochondria also supplies local energy needs [2]. The second major role for active transport is the communication of intracellular signals from the distal axon to the soma, allowing the neuron to respond to changes in environment. While defects in either supply or clearance can readily be predicted to be deleterious to the health of the neuron, there has been a growing appreciation that the propagation of stress signaling along the axon may be a key neurodegenerative pathway leading to cell death [3,4].Here, we focus on recent progress linking defects in fast axonal transport to the pathogenesis of neurodegenerative diseases (reviewed in Table I). Observations from cellular and animal models have provided evidence for multiple alterations in axonal transport, including impaired organelle motility, defects in degradative pathways, impaired neurotrophic signaling, and elevated stress signaling. While it is likely that several cellular pathways may contribute to distal degeneration, recent progress suggests that changes in the balance of signaling along the

Autophagosome dynamics in neurodegeneration at a glance

“…Cargos move differentially along the axon; whereas mitochondria and lysosomes move bidirectionally, APP and dense core vesicles move predominantly in the anterograde direction, and signaling endosome transport is primarily retrograde. Efficient axonal transport is crucial to supply the distal synapse with newly synthesized material, and to clear damaged proteins and organelles Perlson et al, 2010). Not surprisingly, mutations in motor proteins lead to neurodegeneration (Farrer et al, 2009;Puls et al, 2003;Zhao et al, 2001).…”

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

“…The molecular motor kinesin drives transport from the cell body to the nerve periphery, supplying proteins, lipids, RNAs, and other essential materials to the synapse. The dynein/dynactin protein complex drives retrograde transport, moving damaged proteins for degradation, as well as critical signaling molecules such as neurotrophins, to the cell body (3). Dynein is a pleiotropic cellular motor, whose function in numerous cellular pathways may be regulated by specific interactions with different binding partners (4,5).…”

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

“…The size of the neuronal soma pales in comparison with the area covered by axons and dendrites, and consequently, elevated Aβ 1-42 levels in the central nervous system will most frequently first be encountered by neurites, and pathogenic signaling mechanisms will initially be triggered within axons and dendrites. Indeed, many pathogenic alterations in AD, including tau hyperphosphorylation and synaptic changes, occur first in axons or dendrites, respectively [47,48]. However, the pathogenic changes elicited by locally sensed Aβ are not restricted to neurites but are propagated retrogradely to the neuronal soma.…”