Investigating Mechanisms of Neuroplasticity in a Midbrain Organoid Model of Parkinson’s Disease
Pathologically, Parkinson’s disease (PD) is characterized by degeneration of midbrain dopaminergic (mDA) neurons and the presence of intraneuronal inclusions that mainly comprise alpha-synuclein. Mounting evidence suggests that prior to degeneration, the deposition of alpha-synuclein aggregates may lead to system-level disturbances in neuronal networks. We hypothesize that reduced neuronal plasticity precedes the degeneration of mDA neurons.
To investigate this, midbrain organoids are generated from PD patient induced pluripotent stem cell lines with mutations in the SNCA gene, along with sex-age matched control lines to investigate phenotypes related to neuronal plasticity. We investigate differences between wild type and mutant organoids with respect to neural stem cell activity, neuronal and astrocytic development at different stages of organoid maturation by assessing the expression of key markers using immunofluorescence stainings and Western blots. Organoids derived from PD patients with the SNCA triplication mutation show early neuronal differentiation in comparison to healthy controls, as well as reduced astrocyte specification. They also show gross differences in size and morphology, with PD organoids generally being smaller and showing a distinct unbranched neurite phenotype. Our findings suggest that mutations in alpha-synuclein disrupt the normal development of midbrain organoids, suggesting that these mutations may have an impact on neuronal plasticity during brain development, increasing vulnerability to degeneration.