| Description of the project: | Investigating NAD+ Metabolism Role in Alpha-Synuclein Proteostasis and Immune Homeostasis in Parkinson’s Disease Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor dysfunctions, non-motor symptoms, and significantly impacting patients’ quality of life. Key features of PD pathology include alpha-synuclein (α-Syn) aggregation, mitochondrial dysfunction, and neuroinflammation, however, the causal link among those is still unclear. Recent research has focused on the role of NAD+ metabolism in PD. NAD+ is a coenzyme that participates in several cellular processes, such as energy metabolism, DNA repair, and cell survival. Notably, NAD+ levels decline with age, which is the primary risk factor for PD onset and progression. Studies on PD models have indicated a correlation between reduced NAD+ levels and mitochondrial dysfunction. In addition, alterations in NAD+ metabolism have been linked with synucleinopathies and supplementation with NAD+ precursors can alleviate phenotypes associated with impaired NAD+ metabolism in PD models. In this project, we will develop induced pluripotent stem cell (iPSC) derived midbrain organoids from PD patient and healthy control lines. We will then treat midbrain organoids with NAD+ precursors and conduct a comprehensive multiomics analysis to understand the molecular and metabolic changes in response to NAD+ supplementation. Our central objectives are to investigate the relationship between NAD+ metabolism, alpha-synuclein proteostasis, and neuroinflammation in PD, and to explore the therapeutic potential of NAD+ in PD. |
