Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity

Kelley C. O'Donnell, Aaron Lulla, Mark C. Stahl, Nickolas D. Wheat, Jeff M. Bronstein, Alvaro Sagasti

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)571-582
Number of pages12
JournalDMM Disease Models and Mechanisms
Volume7
Issue number5
DOIs
StatePublished - May 2014

Fingerprint

Synucleins
Zebrafish
Axons
Toxicity
Cell death
Pathology
Cell Death
Neurons
Fertilization
Time-Lapse Imaging
Wallerian Degeneration
Imaging techniques
Animal Disease Models
Lewy Body Disease
Detoxification
Poisons
Dopaminergic Neurons
Organelle Biogenesis
Sensory Receptor Cells
Parkinson Disease

All Science Journal Classification (ASJC) codes

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

O'Donnell, Kelley C. ; Lulla, Aaron ; Stahl, Mark C. ; Wheat, Nickolas D. ; Bronstein, Jeff M. ; Sagasti, Alvaro. / Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity. In: DMM Disease Models and Mechanisms. 2014 ; Vol. 7, No. 5. pp. 571-582.
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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.",
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Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity. / O'Donnell, Kelley C.; Lulla, Aaron; Stahl, Mark C.; Wheat, Nickolas D.; Bronstein, Jeff M.; Sagasti, Alvaro.

In: DMM Disease Models and Mechanisms, Vol. 7, No. 5, 05.2014, p. 571-582.

Research output: Contribution to journalArticle

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T1 - Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity

AU - O'Donnell, Kelley C.

AU - Lulla, Aaron

AU - Stahl, Mark C.

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AU - Bronstein, Jeff M.

AU - Sagasti, Alvaro

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