Stem cell-based models to study cellular alterations in Parkinson’s Disease

Sammanfattning: Parkinson’s Disease (PD) is the most prevalent neurodegenerative movement disorder. Despite investigative efforts into the pathogenesis of the disease, the aetiology and mechanism of PD remains unknown, with multiple factors and cellular pathways known to play a part. But the genetic component of the disease, as well as enhanced vulnerability of the midbrain dopaminergic neurons of the Substantia nigra pars compacta make PD a suitable candidate for stem cell-based studies of the disease initiation and progression.The work presented in this thesis aims to generate and utilize PD patient-derived induced pluripotent stem cells (iPSCs), making it possible to assess cellular alterations among patients with different genetic disease backgrounds and disease phenotypes. We also highlight the potential role of other brain cell types, particularly glial cells, in the PD pathogenesis, and employ the same iPSC-based strategies to derive oligodendrocytes, a cell type not well-studied in relation to PD.Our work demonstrated that as oligodendrocytes express synuclein-alpha (SNCA), the expression of PD-associated genetic variant p.A53T impairs oligodendrocyte maturation. The same effect was observed using mouse embryonic stem cell (mESC)-derived oligodendrocytes from a transgenic mouse model overexpressing human SNCA variant p.A53T. These findings validate the use of stem cells to further investigate oligodendrocyte pathology and its possible implications in the pathogenesis of PD.We also obtained iPSCs from a patient with a novel, not previously characterised variant p.Q811R in the POLG1, a risk factor for PD. Differentiation of these iPSCs into midbrain dopaminergic neuron containing spheroids (MDNS) enabled for the first time to assess the neuronal phenotype of POLG1-related PD, and identified several disease phenotypes, associated with PD, including SNCA pathology, disturbance of dopamine homeostasis and impaired energy metabolism.Using omics approaches for investigation of key altered networks in MDNS in POLG1Q811R and SNCAA53T lines revealed distinct altered pathways, highlighting the heterogeneity and multifactorial nature of PD.