Retrograde Axonal Degeneration in Parkinson Disease

Abstract

In spite of tremendous research efforts we have not yet achieved two of our principal therapeutic goals in the treatment of Parkinson's disease (PD), to prevent its onward progression and to provide restoration of systems that have already been damaged by the time of diagnosis. There are many possible reasons for our inability to make progress. One possibility is that our efforts thus far may not have been directed towards the appropriate cellular compartments. Up until now research has been largely focused on the loss of neurons in the disease. Thus, neuroprotection approaches have been largely aimed at blocking mechanisms that lead to destruction of the neuronal cell body. Attempts to provide neurorestoration have been almost entirely focused on replacement of neurons. We herein review the evidence that the axonal component of diseased neuronal systems merit more of our attention. Evidence from imaging studies, from postmortem neurochemical studies, and from genetic animal models suggests that the axons of the dopaminergic system are involved predominantly and early in PD. Since the mechanisms of axonal destruction are distinct from those of neuron cell body degeneration, a focus on axonal neurobiology will offer new opportunities for preventing their degeneration. At present these mechanisms remain largely obscure. However, defining them is likely to offer new opportunities for neuroprotection. In relation to neurorestoration, while it has been classically believed that neurons of the adult central nervous system are incapable of new axon growth, recent evidence shows that this is not true for the dopaminergic projection. In conclusion, the neurobiology of axons is likely to offer many new approaches to protective and restorative therapeutics.

Keywords: Axons; Wallerian degeneration; autophagy; neurodegeneration.

Fig.1

Each panel shows nigrostriatal axons in the MFB visualized by confocal microscopy in TH-GFP mice. Following deletion of Atg7, axons of SNpc dopamine neurons are resistant to retrograde axon degeneration. In the absence of AAV Cre injection, Atg7^fl/fl:TH-GFP mice show a loss of MFB dopaminergic axons, and the appearance of axonal spheroid pathology (red arrows) following unilateral 6OHDA injection. Atg7^wt/wt:TH-GFP mice injected with AAV Cre show a similar axon loss and pathology. However, following injection of AAV Cre, Atg7^fl/fl:TH-GFP mice show minimal axon loss and pathology following 6OHDA injection. Atg7^fl/fl:TH-GFP mice without AAV Cre (n = 5) and Atg7^wt/wt:TH-GFP mice given AAV Cre (n = 6) show a mean loss of 31 (or 32% ) and 32 (or 34% ) MFB axons respectively, whereas Atg7^fl/fl:TH-GFP mice treated with AAV Cre (n = 6) show a mean loss of only 5 (or 5% ) (p <  0.001, ANOVA).

Fig.2

Transmission electron microscopic analysis of axonal spheroids in the medial forebrain bundle in the hLRRK2(R1441G) BAC transgenic mice revealed the presence of giant axonal spheroids containing large numbers of autophagic vacuoles. In A, a thinly myelinated axon (arrowheads) with well-organized cytoskeletal elements leads into a large spheroid that lacks myelin, contains disorganized cytoskeletal structures and is packed with autophagic vacuoles. The region in the white box is shown at higher magnification in B. Numerous vacuoles with double membranes, characteristic of autophagic vacuoles (AV), are observed. Interspersed among them are numerous multilamellar bodies (MLB).