Age-related nigral downregulation of the Parkinson’s risk factor FAM49B primes human microglia for inflammaging

Parkinson’s Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which is associated with changes in microglia function. While age remains the biggest risk factor, the underlying molecular cause of PD onset and its concurrent neuroinflammation are not well understood. Many identified PD risk genes have been directly linked to dopamine neuron impairment, while others are linked to immune cell function. In this study, we found that the PD risk gene FAM49B is critically expressed in microglia of the human SNpc and is downregulated with age. We utilized human and murine microglia cells to demonstrate the role of FAM49B in regulating fundamental microglial functions such as cytoskeletal maintenance, migration, surface adherence, energy homeostasis, endocytosis, and, importantly, inflammatory response. Downregulation of microglial FAM49B, as observed in the SNpc of aging individuals, led to significant alterations in these cellular functions, ultimately resulting in microglia impairment and over-responsiveness. Thus, our study highlights novel cell type-specific roles of FAM49B and provides a potential mechanism for susceptibility to neuroinflammation, and reactive gliosis observed in both PD and normal aging.