Year: 2014
Type: dissertation
Abstract: Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are a\ngrowing problem in an ageing population, but are currently untreatable from the point\nwhen neurons are lost, as these cannot be replaced. However, changes prior to this\npoint common to various neurodegenerative diseases, including synapse loss and\ninhibition of translation, can be reversed, and in the case of translational changes this\nreversal can completely stop further disease progression in some models. With this in\nmind, this project uses prion disease in mice as a predictable, well defined model of\nneurodegenerative diseases to investigate what changes, particularly in protein\nsynthesis, take place at the synapse early in the disease, and how this may contribute to\nongoing pathology. In order to do this more effectively, a protocol was developed to\nefficiently isolate intact synapses from whole hippocampal tissue in sufficient volume\nfor further experimentation, consistently and with minimal contamination from cell\nbody or glial proteins. At the same time, microarray analysis of polysomal and subpolysomal\nRNA from hippocampi of wild-type and prion inoculated mice was carried\nout, in order to examine global changes in polysome association of different RNAs, a\ncorrelate of rate of translation. Changes in polysome association were seen in RNAs\npreviously associated with neurodegenerative diseases and synaptic function, with a\nparticularly significant change seen in the translation of ribosomal sub-units. This\nincluded a large number of mRNAs which are specifically regulated by the mTOR\npathway, TOP (terminal oligopyrimidine) mRNAs. In neurons, the mTOR pathway is\nassociated with regulation of cellular growth, apoptosis, synaptic plasticity and\ntranslation. Changes were seen in the phosphorylation of proteins in this pathway,\nsuggesting altered activation in early prion disease which could be associated with\nsynaptic and translational deficits. This suggests a possible new target for manipulation\nin order to better understand and treat later neurodegeneration.
Source: Figshare
Author: Jason Morgan (6987383)
Institution: University of Leicester
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2404191896