Parkinson’s Disease (PD) is a neurodegenerative disorder characterised by progressive and selective neuronal loss of specific brain regions, including brainstem and cortical regions. Mutations and/or deletions in specific genes result in a high probability of developing PD characterised by distinct presentation. For example, complete loss of parkin function (PRKN KO) causes early onset PD and motor deficits due to the ventral midbrain dopaminergic neurons (VmDA) degeneration. Patients with disease-causing mutations in SCNA and LRRK2 genes show a widespread pathology with high aggregate burden involving monoaminergic cells and other neuronal systems such as the cortex. Nowadays, the study of PD is limited to in vitro and human post-mortem brain studies. These approaches, although fundamental, limited the comprehension of the disease progression because they investigate only the first and latest stages of the disease. In this study, we propose to derive VmDA and cortical neurons from both patient-derived iPSCs and control lines and transplant the cells in a human-mouse chimera model to elucidate the key determinants of disease pathogenesis and progression over extended timeframes in living brain. In addition, we perform a deep cell characterisation to identify distinctive hallmarks specifically related to the disease pathology.Our results show successful derivation and long-term survival both from control and patient VmDA and cortical neurons. In addition, patient-derived cells show a strong disease phenotype comparable with the current knowledge of PD pathology.In conclusion, this study represents an invaluable starting point for future studies investigating PD pathobiology.