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Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.
- Source :
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PLoS genetics [PLoS Genet] 2012; Vol. 8 (8), pp. e1002936. Date of Electronic Publication: 2012 Aug 30. - Publication Year :
- 2012
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Abstract
- Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Aldehyde Dehydrogenase genetics
Aldehyde Dehydrogenase metabolism
Animals
Axons metabolism
Axons pathology
Axons physiology
Calbindin 2
Drosophila Proteins genetics
Drosophila Proteins metabolism
HSP40 Heat-Shock Proteins genetics
HSP40 Heat-Shock Proteins metabolism
Huntington Disease genetics
Huntington Disease metabolism
Mice
Molecular Chaperones genetics
Molecular Chaperones metabolism
Mutation
Proteomics
S100 Calcium Binding Protein G genetics
S100 Calcium Binding Protein G metabolism
Spinocerebellar Ataxias genetics
Spinocerebellar Ataxias metabolism
Thiolester Hydrolases genetics
Thiolester Hydrolases metabolism
Wallerian Degeneration metabolism
Wallerian Degeneration pathology
rho-Associated Kinases genetics
rho-Associated Kinases metabolism
Brain Injuries metabolism
Brain Injuries pathology
Drosophila genetics
Drosophila physiology
Nerve Degeneration metabolism
Nerve Degeneration pathology
Synapses metabolism
Synapses pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 8
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 22952455
- Full Text :
- https://doi.org/10.1371/journal.pgen.1002936