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Nat Neurosci. 2015 Sep;18(9):1325-33. doi: 10.1038/nn.4070. Epub 2015 Jul 27.

Identification of neurodegenerative factors using translatome-regulatory network analysis.

Author information

1
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
2
Department of Systems Biology, Columbia University, New York, New York, USA.
3
Department of Biological Sciences, Columbia University, New York, New York, USA.
4
Department of Neurology, Columbia University, New York, New York, USA.
5
Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
6
Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA.
7
Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA.

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.

PMID:
26214373
PMCID:
PMC4763340
DOI:
10.1038/nn.4070
[Indexed for MEDLINE]
Free PMC Article

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