title: Identification of neurodegenerative factors using translatome-regulatory network analysis.
abstract: For degenerative disorders of the CNS, the main obstacle to therapeutic advancement has been the challenge of identifying the key molecular mechanisms underlying neuronal loss. We developed a combinatorial approach including translational profiling and brain regulatory network analysis to search for key determinants of neuronal survival or death. Following the generation of transgenic mice for cell type-specific profiling of midbrain dopaminergic neurons, we established and compared translatome libraries reflecting the molecular signature of these cells at baseline or under degenerative stress. Analysis of these libraries by interrogating a context-specific brain regulatory network led to the identification of a repertoire of intrinsic upstream regulators that drive the dopaminergic stress response. The altered activity of these regulators was not associated with changes in their expression levels. This strategy can be generalized for the identification of molecular determinants involved in the degeneration of other classes of neurons.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Brichta
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, USA.|Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: William
authors.initials: W
authors.lastname: Shin
authors.affiliation: Department of Neurology, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.|Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA.|Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA.
authors.forename: Vernice
authors.initials: V
authors.lastname: Jackson-Lewis
authors.affiliation: Department of Neurology, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.|Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA.|Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Blesa
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Ee-Lynn
authors.initials: EL
authors.lastname: Yap
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Walker
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Jack
authors.identifier: http://orcid.org/0000-0001-8766-1749
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Roussarie
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Mariano J
authors.identifier: http://orcid.org/0000-0002-7503-2491
authors.initials: MJ
authors.lastname: Alvarez
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Department of Neurology, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.|Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA.|Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology