Genetics and Molecular Pathways in Parkinson's disease and Parkinsonism

Abstract

In this thesis I used a wide range of genetic methodologies and biological strategies to unravel the genetic bases of parkinsonian disorders and their clinical relevance. First, in Paper I, we present the discovery of a novel genetic cause (DNAJC13 p.N855S) of late-onset autosomal dominant Parkinson’s disease (PD). This mutation, when expressed, causes alterations in trafficking of proteins from the cell membrane. Subsequently, in Paper II, we show that DNAJC13 harbor additional genetic risk variants in PD and atypical parkinsonism which suggests that deficits in endosomal protein recycling and trafficking might be involved in a spectrum of parkinsonian disorders. This analysis was further extended to the retromer complex components (VPS26A/B, VPS29 and VPS35) in Paper III. Retromer has previously been linked to PD through the identification of VPS35 p.D620N as a disease-causing mutation. We identified three VPS26A variants (p.K93E, p.M112V, p.K297X), in patients with atypical parkinsonism, one of which has later been shown to disrupt the interaction with a known retromer cargo protein. In Paper IV we identified DCTN1 p.K56R in patients with Progressive supranuclear palsy. This mutation is immediately adjacent to the N-terminal p150glued ‘CAP-Gly’ domain, affects a highly conserved amino acid and alters the protein's affinity to microtubules and its cytoplasmic distribution. Collectively, these studies support the notion that intracellular trafficking is involved in the development of parkinsonism. Then, in Paper V, we elucidate the genetic etiology of parkinsonism in patients with early onset disease. We found that 14% of patients carried mutations linked to monogenic parkinsonism. We assess the usefulness genetic screening as a diagnostic tool and the possibility using genetic information to predict disease progression and found that GBA mutation carriers were most likely to suffer an earlier cognitive demise. Finally, in Paper VI, we describe the identification of mutations in NOVA2 and SPATS2 as novel potential causes of PD and dementia. Both NOVA2 and SPATS2 are RNA-binding proteins and hence, highlight mRNA regulation as an avenue to explore in the pathogenesis of disease.