The neuronal nucleus is highly specialized with a unique and characteristic organization of the genome, transcription and epigenetic regulation. Little is known about its chromatin organization as most studies have focused on rapidly growing and dividing cells. This study has determined the ultrastructural and molecular organization of the mouse striatal neuronal nucleus and to correlate this with the distribution of a range of epigenetic modifications. The relationship of the structural organization to a functional assay of in vivo transcription detecting nascent RNA together with the localization of RNA pol I, II and III have been explored. These provide strikingly different results to the literature, foremost is the highest level of transcription mediated by RNA pol III within the perinucleolar heterochromatin. A novel mechanistic theory of the neuronal nucleolar complex is postulated which may underlie the establishment and maintenance of the post-mitotic, non-regenerating and growth restricted status of neurons. Surprisingly, this unique neuronal nucleolar complex appears to be a focus for disorganization upon HDAC inhibition and in various neurodegenerative disease models. The cellular process observed for the extrusion of TDP-43 aggregates out of the neurons in the novel TDP-43M337V transgenic mouse models of ALS/FTLD further implicates a novel mechanism for the extracellular spread of transmissible proteinopathies. In agreement with recent literature, it is speculated that prion-like propagation involving RNA-binding proteins with putative prion domains might underlie the cell-to-cell emanation of neurodegenerative pathology throughout the nervous system.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:625990 |
| Date | January 2013 |
| Creators | So, E. W. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1390625/ |
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