The Wld(S) mutation delays anterograde, but not retrograde, axonal degeneration of the dopaminergic nigro-striatal pathway in vivo.
For many neurodegenerative disorders, such as Parkinson's disease, there is evidence that the disease first affects axons and terminals of neurons that are selectively vulnerable. This would suggest that it may be possible to forestall progression by targeting the cellular mechanisms of axon degeneration. While it is now clear that these mechanisms are distinct from the pathways of programmed cell death, they are less well known. Compelling evidence of the distinctiveness of these mechanisms has derived from studies of the Wld(S) mutation, which confers resistance to axon degeneration. Little is known about how this mutation affects degeneration in dopaminergic axons, those that are affected in Parkinson's disease. We have characterized the Wld(S) phenotype in these axons in four models of injury: two that utilize the neurotoxin 6-hydroxydopamine or axotomy to induce anterograde degeneration, and two that use these methods to induce retrograde degeneration. For both 6-hydroxydopamine and axotomy, Wld(S) provides protection from anterograde, but not retrograde degeneration. This protection is observed as preserved immunostaining for tyrosine hydroxylase in axons and striatum, and by structural integrity visualized by GFP in tyrosine hydroxylase-GFP mice. Therefore, Wld(S) offers axon protection, but it reveals fundamentally different processes underlying antero- and retrograde degeneration in this system.
Cheng
Hsiao-Chun
HC
Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Burke
Robert E
RE
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001369:Axons / Q000473:pathology*; D019771:Axotomy; D004298:Dopamine / Q000502:physiology*; D005260:Female; D049452:Green Fluorescent Proteins; D006892:Hydroxydopamines / Q000633:toxicity; D007150:Immunohistochemistry; D008474:Medial Forebrain Bundle / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009154:Mutation / Q000502:physiology*; D017072:Neostriatum / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009434:Neural Pathways / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013378:Substantia Nigra / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D006892:Hydroxydopamines; D009419:Nerve Tissue Proteins; C442580:Wld protein, mouse; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine