Kara, E; (2014) The genetic basis and pathogenesis of Parkinson's disease and complex parkinsonisms. Doctoral thesis , UCL (University College London).

Abstract

In my thesis, I examined the genetic basis and pathogenesis of complex parkinsonisms and Parkinson's disease. First, I studied a cohort of sporadic and familial cases with dystonia-parkinsonism syndromes with a focus on WDR45 and FBXO7 mutations. Second, I studied the role of α-synuclein (SNCA) mutations in the pathogenesis of synucleinopathies, work that lead to the discovery of the novel G51D SNCA mutation. I further characterised the biochemical properties of this mutation that indicated differences in comparison to the A53T mutation. I also described a family carrying a duplication of the SNCA locus and undertook a metaanalysis of published cases with SNCA duplications to determine phenotype-genotype correlations. Third, I studied the role of MAPT mutations in the pathogenesis of cases with parkinsonism and tau in neuropathology. This analysis lead to the discovery of the first risk variant within MAPT, A152T, and of a case with a LRRK2 mutation with tau pathology and a novel MAPT variant, suggesting that such variants could predispose to the development of tau pathology and unusual clinical features. Fifth, I completed a GWAS for Parkinson's disease in the Greek population and confirmed that risk factors reported in Northern European and American populations are also applicable to Greece. This is important as genetic risk factors could be used in the future to predict disease status. Sixth, I studied the role of CSF1R mutations in the pathogenesis of leukoencephalopathies and found that they account for a substantial proportion of the disease and are occasionally associated with clinical features resembling complex parkinsonisms. Finally, I assessed autophagic dysfunction in patient-derived fibroblasts with SPG11 mutations and studied the function of SPATACSIN in an unbiased way using gene expression network analysis. In summary, this data provide insight into the genetic basis and pathogenetic mechanisms of parkinsonisms and indicate that there could be overlap in pathogenesis with dementias.

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