The behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s disease
<p>Mutations in the leucine-rich repeat kinase II (<em>LRRK2</em>) gene cause autosomal-dominant Parkinson’s disease (PD) which is indistinguishable from sporadic forms of the disease. However, the mechanism by which <em>LRRK2</em> mutation promotes PD pathology and the...
| প্রধান লেখক: | , |
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| অন্যান্য লেখক: | |
| বিন্যাস: | গবেষণাপত্র |
| ভাষা: | English |
| প্রকাশিত: |
2014
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| বিষয়গুলি: |
| _version_ | 1826294933094400000 |
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| author | Sloan, M Maximilian Sloan |
| author2 | Wade-Martins, R |
| author_facet | Wade-Martins, R Sloan, M Maximilian Sloan |
| author_sort | Sloan, M |
| collection | OXFORD |
| description | <p>Mutations in the leucine-rich repeat kinase II (<em>LRRK2</em>) gene cause autosomal-dominant Parkinson’s disease (PD) which is indistinguishable from sporadic forms of the disease. However, the mechanism by which <em>LRRK2</em> mutation promotes PD pathology and the functions of the <em>LRRK2</em> protein itself are currently unknown. Transgenic animal models, expressing PD-linked genes, have been crucial in developing a clearer picture of the mechanisms behind PD progression. Bacterial artificial chromosome (BAC) transgenics, in particular, allow for physiologically relevant disease models to be generated, encompassing entire gene sequences and using endogenous promoters, which result in an accurate recapitulation of spatiotemporal gene expression. We have, therefore, developed BAC transgenic rats expressing human <em>LRRK2</em>. These lines express either human wild-type, G2019S mutant (the most common <em>LRRK2</em> mutation) or R1441C mutant (the <em>LRRK2</em> mutation leading to a more aggressive pathology) <em>LRRK2</em>. These rats display <em>LRRK2</em> transgene expression patterns in the brain which highly resemble human <em>LRRK2</em> expression. We subsequently aged these lines for the purposes of behavioural and molecular analysis. Additionally, we have performed a number of in vitro studies in neurons cultured from these rats to further investigate the effects of pathological forms of <em>LRRK2</em>. Mutant <em>LRRK2</em> transgenic rats displayed progressively impaired striatal dopaminergic release along with corresponding behavioural deficits, both motor and cognitive. These motor deficits could be rescued by treatment with levodopa, implying a similar underlying pathological process to PD. These phenotypes occurred in the absence of any overt degeneration of the dopaminergic neurons of the substantia nigra pars compacta or other PD-associated neuropathological markers. We also detected a number of molecular alterations associated with mutant <em>LRRK2</em> expression including altered <em>LRRK2</em> phosphorylation and in vitro evidence of altered autophagic processes. In conclusion, these rats recapitulate a number of the key features of Parkinson’s disease and provide clues as to the progression of pathology in PD.</p> |
| first_indexed | 2024-03-07T03:53:20Z |
| format | Thesis |
| id | oxford-uuid:c2058b71-df43-47cd-a794-13184bacf313 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:53:20Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:c2058b71-df43-47cd-a794-13184bacf3132022-03-27T06:05:56ZThe behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s diseaseThesishttp://purl.org/coar/resource_type/c_db06uuid:c2058b71-df43-47cd-a794-13184bacf313NeuropathologyNeurogeneticsEnglishOxford University Research Archive - Valet2014Sloan, MMaximilian SloanWade-Martins, R<p>Mutations in the leucine-rich repeat kinase II (<em>LRRK2</em>) gene cause autosomal-dominant Parkinson’s disease (PD) which is indistinguishable from sporadic forms of the disease. However, the mechanism by which <em>LRRK2</em> mutation promotes PD pathology and the functions of the <em>LRRK2</em> protein itself are currently unknown. Transgenic animal models, expressing PD-linked genes, have been crucial in developing a clearer picture of the mechanisms behind PD progression. Bacterial artificial chromosome (BAC) transgenics, in particular, allow for physiologically relevant disease models to be generated, encompassing entire gene sequences and using endogenous promoters, which result in an accurate recapitulation of spatiotemporal gene expression. We have, therefore, developed BAC transgenic rats expressing human <em>LRRK2</em>. These lines express either human wild-type, G2019S mutant (the most common <em>LRRK2</em> mutation) or R1441C mutant (the <em>LRRK2</em> mutation leading to a more aggressive pathology) <em>LRRK2</em>. These rats display <em>LRRK2</em> transgene expression patterns in the brain which highly resemble human <em>LRRK2</em> expression. We subsequently aged these lines for the purposes of behavioural and molecular analysis. Additionally, we have performed a number of in vitro studies in neurons cultured from these rats to further investigate the effects of pathological forms of <em>LRRK2</em>. Mutant <em>LRRK2</em> transgenic rats displayed progressively impaired striatal dopaminergic release along with corresponding behavioural deficits, both motor and cognitive. These motor deficits could be rescued by treatment with levodopa, implying a similar underlying pathological process to PD. These phenotypes occurred in the absence of any overt degeneration of the dopaminergic neurons of the substantia nigra pars compacta or other PD-associated neuropathological markers. We also detected a number of molecular alterations associated with mutant <em>LRRK2</em> expression including altered <em>LRRK2</em> phosphorylation and in vitro evidence of altered autophagic processes. In conclusion, these rats recapitulate a number of the key features of Parkinson’s disease and provide clues as to the progression of pathology in PD.</p> |
| spellingShingle | Neuropathology Neurogenetics Sloan, M Maximilian Sloan The behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s disease |
| title | The behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s disease |
| title_full | The behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s disease |
| title_fullStr | The behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s disease |
| title_full_unstemmed | The behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s disease |
| title_short | The behavioural and molecular characterisation of a novel LRRK2 BAC transgenic rat model of Parkinson’s disease |
| title_sort | behavioural and molecular characterisation of a novel lrrk2 bac transgenic rat model of parkinson s disease |
| topic | Neuropathology Neurogenetics |
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