Parkinson’s disease (PD) is the second most common neurodegenerative condition, with serious negative impacts on quality of life, as well as financial and personal burden on sufferers and caregivers. There remains no disease modifying therapy. PD is strongly linked to aberrant oligomerization and accumulation of alpha-synuclein (αsyn) protein. Mesenchymal stem cells (MSCs) are multipotent cells that can be isolated from vascularized tissue throughout the body and exert regenerative effects through their dynamic secretome, which is influenced by multiple factors including their microenvironment and any surrounding pathology. In this proposal, we hypothesize that by conditioning MSCs with PD-simulating stimuli, both chemical and patient-derived, we will enrich their secretome for factors which are particularly beneficial in combating αsyn-associated pathology. The potency of conditioned MSCs in targeting αsyn pathology will be assessed using biochemical and staining methods, using protein complementation, semi-native western blot and immunohistochemical analysis of oligomeric αsyn in cellular models of synucleinopathy, as well as assessing toxicity. By comparative proteomic analysis of the MSC secretome in the presence and absence of PD-simulating stimuli we will identify these beneficial secreted molecules and validate them for efficacy in alleviating αsyn-associated pathology in cellular models of synucleinopathy. For the K00 portion of this proposal, focus shifts to Alzheimer’s disease (AD), an even more common neurodegenerative condition with no meaningful therapeutic interventions. Clinical trials based on rodent studies fail to translate efficacy to human subjects, highlighting the need for physiologically relevant translatable models. Further, genetic association studies have highlighted more than 20 risk loci, usually relatively common but with moderate effect sizes. In order to mechanistically probe these different genetic risk factors in a relevant, pathology-developing model we propose to generate human brain organoids from iPSCs, gene edited to reflect various distinct genetic risk profiles. We will perform longitudinal comparative transcriptomics (RNAseq) to identify common and distinct pathways associated with the progression of pathology in these models and determine therapeutic targets which may be generalizable to AD or specific to certain genetic backgrounds.