| Summary: | Parkinson's disease is a neurodegenerative disorder that is pathologically characterised by the preferential cell death of vulnerable dopaminergic neurons (DAn) in the midbrain. Multiplications of the human alpha-Synuclein (aSyn) gene locus give rise to autosomal-dominant Parkinson's and elevated aSyn expression has been linked to an increased risk to develop sporadic Parkinson's. Thus, aSyn provides an important link between familial and sporadic forms of the disease. This thesis brings together cutting-edge transgenic mouse models to examine early translational changes in the specifically vulnerable DAn. Translating ribosome affinity purification (TRAP) methodology was combined with a mouse model of Parkinson's that over-expresses aSyn from the complete human SNCA locus. Immunoprecipitation of translated mRNA from midbrain DAn enabled the investigation of perturbations in gene expression early during disease progression. Next generation sequencing analysis of translated mRNAs determined the effect of aSyn over-expression on the translational profile of the "at-risk" population of DAn. This translatome analysis in THTR mice which express an eGFP-tagged ribosomal transgene (eGFP-L10a) under the endogenous mouse promoter of tyrosine hydroxylase (TH) identified a mitochondrial deficit in aged transgenic mice. In addition, a novel Cre-conditional TRAP line expresses eGFP-L10a inCre expressing cells upon crossing to a DAT-Cre driver. Pilot TRAP experiments successfully isolated translated mRNA from soma (midbrain) and axons (striatum) of DAn. Overall, data generated with the transgenic TRAP/Parkinson's mouse lines will allow to obtain a more complete understanding of the underlying pathological pathways and translational changes during Parkinson's.
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