LRRK2 genetics and expression in the Parkinsonian brain.
Doctoral thesis, UCL (University College London).
Mutations in LRRK2 have been established as a common genetic cause of Parkinson’s disease (PD). Variation in gene expression of PARK loci has previously been demonstrated in PD pathogenesis, although it has not been described in detail for LRRK2 expression in the human brain. This study further elucidates the role of LRRK2 in development of PD by describing an investigation into the role of LRRK2 genetics and expression in the human brain. The G2019S mutation is a common LRRK2 mutation that exhibits a clinical and pathological phenotype indistinguishable from idiopathic PD. Thus, the study of G2019S mutation is a recurrent theme. The frequency of G2019S was estimated in unaffected subjects that lived or shared a cultural heritage to the predicted founding populations of the mutation, and was found not to be common in these populations. Morphological analysis revealed a ubiquitous expression for LRRK2 mRNA and protein in the human brain. In-situ hybridisation data suggests that LRRK2 mRNA is present as a low copy number mRNA in the human brain. A semi-quantitative analysis of LRRK2 immunohistochemistry revealed extensive regional variation in the LRRK2 protein levels, although the weakest immunoreactivity was consistently identified in the nigrostriatal dopamine region. No difference was observed in the morphological localisation of LRRK2 mRNA and protein in unaffected, IPD or G2019S positive PD subjects. Dysregulation of LRRK2 mRNA expression and the effects of cis- acting genetic variation on these levels were demonstrated. A widespread decrease of LRRK2 mRNA was observed in IPD and G2019S positive PD subjects in comparison to unaffected controls. Furthermore, non-coding genetic variation was also demonstrated to have an effect on the LRRK2 transcriptional activity in PD subjects. Collectively, these findings suggest that LRRK2 has an important physiological role, and a dysregulation in its levels could affect auxiliary mechanisms that contribute to PD pathogenesis. This data also supports the possibility of a shared mechanism contributing to the identical phenotype of IPD and G2019S linked PD.
|Title:||LRRK2 genetics and expression in the Parkinsonian brain|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience|
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