Parkinson’s disease: understanding disease pathogenesis by different model systems

Parkinson Disease (PD) is a neurodegenerative disease caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and characterized by resting tremor, bradykinesia, rigidity, and postural instability. PD is a complex disease caused by the combination of environmental and genetic determinants. In the last 20 years considerable progresses have been made in the identification of the genetic components of PD: different genes were shown to cause rare monogenic forms of PD, while a larger number of predisposing genetic variants have been associated with sporadic PD. Among them, GBA is recognized as the main risk factor for PD. Despite these advancements, a large fraction of the expected PD heritability is still missing and the main risk factor is still represented by the age. As for the other neurodegenerative disorders, the impossibility to obtain fresh samples makes mandatory the development of models to understand the molecular event underlying the pathology. In this scenario, my thesis aimed to study different PD causes using the most suitable model, when available, or trying to develop a tailored one. Firstly, we studied a monogenic form of PD caused by mutation of the DNAJC12 gene. We evaluated DNAJC12 localization and interaction with its proposed molecular partners in differentiated SH-SY5Y cells confirming its role in the synthesis of dopamine. Then we assessed the DNAJC12 ablation effects in zebrafish embryos highlighting its role in brain development. Second, we focused on GBA-related PD using midbrain organoids derived from GBA mutated patients with PD or Gaucher Disease (GD). We confirmed that the produced organoids have a strong striatal dopaminergic identity both via whole transcriptome analysis and via immunohistochemistry assays. Moreover, we found that this model recapitulates also the donor phenotype showing substrate accumulation in the GD-derived organoids, reduced glucosylcerebrosidase activity and α synuclein accumulation in dopaminergic neurons. In the third part of the thesis, we tried to generate a model recapitulating the neuronal aging process via overexpression of progerin in the SH-SY5Y neuroblastoma cell line. The obtained cells overexpress p21 and show higher level of SAβGal activity suggesting that they undergo to senescence and could represent a promising model to study the transcriptomic changes occurring in aged neurons.