Retrograde axonal transport: pathways to cell death?

Abstract

Active transport along the axon is crucial 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. Although 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.

Fig. 1. Retrograde axonal transport may be altered at multiple levels

Impairment of transport may arise from direct mutations in microtubule motors or their activators and adaptors; mutations in cytoplasmic dynein heavy chain have been identified in the mouse (Loa, Cra1, and Swl), and point mutations in the p150^Glued subunit of dynactin have been identified in humans (G59S, G71R, G71E, G71A, T72P, and Q74P). Changes in the velocity or efficiency of retrograde transport may be induced by changes in cargo adaptors or effectors, such as Rab7/RILP or Huntingtin/HAP1, that coordinate cargo-bound motors. Transport along the axon may also be affected by changes in post-translational modifications of the microtubule track, such as changes in acetylation, tyrosination, or the complement of bound microtubule-associate proteins (MAPs). Finally, pathological changes along the axon, such as remodeling of the cellular cytoskeleton or the development of protein aggregates, may deleteriously affect retrograde axonal transport.

Fig. 2. Changes in retrograde flux along the axon may lead to defects in supply and clearance

Top, Neuronal function and survival depend on retrograde axonal transport driven by the microtubule motor protein dynein and its activator dynactin. Cargos that are actively transported along the axon include transport vesicles, mitochondria, lysosomes, autophagosomes, and signaling endosomes. Bottom, a significant slowing of retrograde axonal transport is observed at early stages of disease in several neurodegenerative models, consistent with a role in pathogenesis. This slowed transport leads to decreased flux, and potentially to defects in supply and clearance. MT: microtubules, oriented with plus (+) ends distal and minus (-) ends proximal to the cell body.

Fig. 3. Changes in retrograde signaling lead to neurodegeneration and cell death

Top, In a healthy neuron, pro-survival signals (green) associated with signaling endosomes, are actively transported from the cell periphery to the nucleus to promote neuron survival. Neurotrophic factors activate downstream effectors such as Trk receptors, which are transported to the soma via a retrograde signaling endosome. During neurodegeneration, bottom, activation of retrograde death pathways (red) in a non-cell autonomous process may activate cell stress pathways and lead to cell death; decreased retrograde flux may also contribute. For instance, p75 cleavage fragment, activated caspase8 and p-JNK are transported to the cell soma to initiate cell stress/death responses in a mouse model of familial ALS [3]. The specific identity of the environmental stress ligands, as well as the specific combinatorial role of the receptors and co-receptors that regulate survival/death pathways, remain to be determined. Examples of possible pro-survival ligands present in a supportive environment are listed in green. Examples of possible pro-death ligands secreted in a stressful environment are listed in red. NT-neurotrophins; p75 cl.fr.- p75 cleavage fragment; MT-microtubules.