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Published October 15, 2013 | public
Journal Article

Transcriptional regulation by nicotine in dopaminergic neurons


Dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate in Parkinson's disease. These neurons robustly express several nicotinic acetylcholine receptor (nAChR) subtypes. Smoking appears to be neuroprotective for Parkinson's disease but the mechanism is unknown. To determine whether chronic nicotine-induced changes in gene expression contribute to the neuroprotective effects of smoking, we develop methods to measure the effect of prolonged nicotine exposure on the SNc neuronal transcriptome in an unbiased manner. Twenty neurons were collected using laser-capture microscopy and transcriptional changes were assessed using RNA deep sequencing. These results are the first whole-transcriptome analyses of chronic nicotinic treatment in SNc neurons. Overall, 129 genes were significantly regulated: 67 upregulated, 62 downregulated. Nicotine-induced relief of endoplasmic reticulum (ER) stress has been postulated as a potential mechanism for the neuroprotective effects of smoking. Chronic nicotine did not significantly affect the expression of ER stress-related genes, nor of dopamine-related or nAChR genes, but it did modulate expression of 129 genes that could be relevant to the neuroprotective effects of smoking, including genes involved in (1) the ubiquitin-proteasome pathway, (2) cell cycle regulation, (3) chromatin modification, and (4) DNA binding and RNA regulation. We also report preliminary transcriptome data for single-cell dopaminergic and GABAergic neurons isolated from midbrain cultures. These novel techniques will facilitate advances in understanding the mechanisms taking place at the cellular level and may have applications elsewhere in the fields of neuroscience and molecular biology. The results give an emerging picture of the role of nicotine on the SNc and on dopaminergic neurons.

Additional Information

© 2013 Elsevier B.V. Received 8 May 2013. Accepted 26 July 2013. Available online 9 August 2013. We thank Igor Antoshechkin for library sequencing, sequencing facility management and for computational training, Sheri McKinney for excellent cell cultures and for conducting nicotine administration, and Purnima Deshpande for animal breeding and laboratory management. We thank Prof. John Allman for use of the Zeiss laser capture microscope, Georgi Marinov for some analysis and helpful discussions and Charlotte Yang for initial DAVID analysis. This work was supported by the NIH (DA017279, AG033954), by the California Tobacco-Related Disease Research Program, by the Caltech Innovation Initiative, and by the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. We thank the reviewers for helpful and insightful comments.

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