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dc.contributor.authorWishart, Thomas M.
dc.contributor.authorRooney, Timothy M.
dc.contributor.authorLamont, Douglas J.
dc.contributor.authorWright, Ann K.
dc.contributor.authorMorgon, A. Jennifer
dc.contributor.authorJackson, Mandy
dc.contributor.authorFreeman, Marc R.
dc.contributor.authorGillingwater, Thomas H.
dc.date2022-08-11T08:09:29.000
dc.date.accessioned2022-08-23T16:32:22Z
dc.date.available2022-08-23T16:32:22Z
dc.date.issued2012-08-30
dc.date.submitted2013-01-23
dc.identifier.citationPLoS Genet. 2012;8(8):e1002936. doi: 10.1371/journal.pgen.1002936. <a href="http://dx.doi.org/10.1371/journal.pgen.1002936" target="_blank">Link to article on publisher's site</a>
dc.identifier.issn1553-7390 (Linking)
dc.identifier.doi10.1371/journal.pgen.1002936
dc.identifier.pmid22952455
dc.identifier.urihttp://hdl.handle.net/20.500.14038/37870
dc.description<p>Co-author Timothy Rooney is a student in the MD/PhD program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.</p>
dc.description.abstractDegeneration 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=22952455&dopt=Abstract">Link to Article in PubMed</a>
dc.rightsCopyright 2012 Wishart et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.subjectAldehyde Dehydrogenase
dc.subjectAnimals
dc.subjectAxons
dc.subject*Brain Injuries
dc.subjectCalcium-Binding Protein, Vitamin D-Dependent
dc.subject*Drosophila
dc.subjectDrosophila Proteins
dc.subjectHSP40 Heat-Shock Proteins
dc.subjectHuntington Disease
dc.subjectMice
dc.subjectMolecular Chaperones
dc.subjectMutation
dc.subject*Nerve Degeneration
dc.subjectProteomics
dc.subjectSpinocerebellar Ataxias
dc.subject*Synapses
dc.subjectThiolester Hydrolases
dc.subjectWallerian Degeneration
dc.subjectrho-Associated Kinases
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectGenetics and Genomics
dc.subjectNeuroscience and Neurobiology
dc.titleCombining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo
dc.typeJournal Article
dc.source.journaltitlePLoS genetics
dc.source.volume8
dc.source.issue8
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1139&amp;context=neurobiology_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/neurobiology_pp/140
dc.identifier.contextkey3608534
refterms.dateFOA2022-08-23T16:32:22Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathneurobiology_pp/140
dc.contributor.departmentGraduate School of Biomedical Sciences, MD/PhD Program
dc.contributor.departmentFreeman Lab
dc.contributor.departmentNeurobiology
dc.source.pagese1002936
dc.contributor.studentTimothy M. Rooney
dc.description.thesisprogramMD/PhD


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