Role of Nucleolus in Neuronal Health and Disease
Hetman Lab Research Area 1: Role of nucleolus in neuronal health and disease.
Nucleolus (a small nucleus or a nucleus of the nucleus) is a nuclear subdomain which is best known for its critical role in ribosome production. Thus, the nucleolus contains tandem repeats of 45S ribosomal RNA genes which are transcribed by a specialized RNA Polymerase-I. In the nucleolus, the primary rRNA transcript is processed into mature 5.8S, 18S and 28S rRNAs. While ribosomal biogenesis is the best known nucleolar function, additional roles for this structure have been also discovered including assembly of various non-ribosomal RNA-protein complexes as well as sequestration/inactivation and/or storage/regulated release of several signaling proteins. Although it is know for nearly 200 years that neurons have prominent nucleoli, the role of this structure in neuronal physiology and pathology remains unknown. Therefore, we investigate the nucleolar contribution to DNA damage signaling in postmitotic neurons. In addition, we probe nucleolar role in neurite extension and maintenance. Finally, we examine the nucleolus as a potential target of pathological cascades that lead to neuronal atrophy or hypertrophy including those that are active in neurodegenerative diseases or epilepsy.
Figure 1. A drawing of a cerebellar Purkinje neuron containing a prominent nucleolus inside the nucleus (Jan Purkinje, 1837).
Figure 2. Nucleoli of primary rat cortical neurons are sensitive to the DNA damaging drug camptothecin (CPT). Neurons were treated with 5 mikroM CPT for 8 hr. Nucleoli were visualized by immunostaining for a nucleolar protein B23 (green) whose nucleolar residence requires active rRNA transcription (modified from Kalita, Hetman et al., 2008).
To learn more, please see:
Hetman M, Pietrzak M. Emerging roles of the neuronal nucleolus. Trends Neurosci. 2012 May;35(5):305-14. doi: 10.1016/j.tins.2012.01.002. Epub 2012 Feb 2. Review. PubMed PMID: 22305768; PubMed Central PMCID: PMC3348388. Pietrzak M, Rempala G, Nelson PT, Zheng JJ, Hetman M. Epigenetic silencing of nucleolar rRNA genes in Alzheimer's disease. PLoS One. 2011;6(7):e22585. doi: 10.1371/journal.pone.0022585. Epub 2011 Jul 22. PubMed PMID: 21799908; PubMed Central PMCID: PMC3142181. Pietrzak M, Smith SC, Geralds JT, Hagg T, Gomes C, Hetman M. Nucleolar disruption and apoptosis are distinct neuronal responses to etoposide-induced DNA damage. J Neurochem. 2011 Jun;117(6):1033-46. doi: 10.1111/j.1471-4159.2011.07279.x. Epub 2011 May 13. PubMed PMID: 21517844; PubMed Central PMCID: PMC3107349. Gomes C, Smith SC, Youssef MN, Zheng JJ, Hagg T, Hetman M. RNA polymerase 1-driven transcription as a mediator of BDNF-induced neurite outgrowth. J Biol Chem. 2011 Feb 11;286(6):4357-63. doi: 10.1074/jbc.M110.170134. Epub 2010 Nov 23. PubMed PMID: 21098478; PubMed Central PMCID: PMC3039349. Hetman M, Vashishta A, Rempala G. Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition. J Neurochem. 2010 Sep;114(6):1537-49. doi: 10.1111/j.1471-4159.2010.06859.x. Epub 2010 Aug 19. Review. PubMed PMID: 20557419; PubMed Central PMCID: PMC2945429. Kalita K, Makonchuk D, Gomes C, Zheng JJ, Hetman M. Inhibition of nucleolar transcription as a trigger for neuronal apoptosis. J Neurochem. 2008 Jun 1;105(6):2286-99. doi: 10.1111/j.1471-4159.2008.05316.x. PubMed PMID: 18315559; PubMed Central PMCID: PMC2909334.