Abstract
α-synuclein (aSyn) expression is implicated in neurodegenerative processes, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). In animal models of these diseases, axon pathology often precedes cell death, raising the question of whether aSyn has compartment-specific toxic effects that could require early and/or independent therapeutic intervention. The relevance of axonal pathology to degeneration can only be addressed through longitudinal, in vivo monitoring of different neuronal compartments. With current imaging methods, dopaminergic neurons do not readily lend themselves to such a task in any vertebrate system. We therefore expressed human wild-type aSyn in zebrafish peripheral sensory neurons, which project elaborate superficial axons that can be continuously imaged in vivo. Axonal outgrowth was normal in these neurons but, by 2 days post-fertilization (dpf), many aSyn-expressing axons became dystrophic, with focal varicosities or diffuse beading. Approximately 20% of aSyn-expressing cells died by 3 dpf. Time-lapse imaging revealed that focal axonal swelling, but not overt fragmentation, usually preceded cell death. Co-expressing aSyn with a mitochondrial reporter revealed deficits in mitochondrial transport and morphology even when axons appeared overtly normal. The axon-protective protein Wallerian degeneration slow (WldS) delayed axon degeneration but not cell death caused by aSyn. By contrast, the transcriptional coactivator PGC-1α, which has roles in the regulation of mitochondrial biogenesis and reactive-oxygen-species detoxification, abrogated aSyn toxicity in both the axon and the cell body. The rapid onset of axonal pathology in this system, and the relatively moderate degree of cell death, provide a new model for the study of aSyn toxicity and protection. Moreover, the accessibility of peripheral sensory axons will allow effects of aSyn to be studied in different neuronal compartments and might have utility in screening for novel disease-modifying compounds.
Highlights
In this study, the authors establish an in vivo model for longitudinally studying the effects of aSyn accumulation on axonal integrity by expressing human wild-type aSyn in zebrafish peripheral sensory neurons, which are accessible to imaging in living animals
Implications and future directions These results suggest that axonopathy is an early consequence of aSyn accumulation, which only sometimes leads to cell death
Because the axonal compartment is especially sensitive to disruptions in mitochondrial function and transport, a better understanding of the relationship between mitochondrial function and axonal integrity could identify new therapeutic targets that act on pathways either upstream of or parallel to cell death
Summary
Aggregate formation in the synapse and axon precedes Lewy body formation and cell death in multiple cell types (Galvin et al, 1999; Orimo et al, 2008; Schulz-Schaeffer, 2010; Nakata et al, 2012). These recent findings have led to the hypothesis that PD degeneration is initiated in the axon (O’Malley, 2010; Burke and O’Malley, 2012). Whether axon degeneration leads to cell death or proceeds independently, is unknown
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