SIRPα deficiency accelerates the pathologic process in models of Parkinson disease

Microglia-mediated neuroinflammation is a crucial pathophysiological contributor to several aging-related neurodegenerative disorders, including Parkinson's disease (PD). During the process of aging or stress, microglia undergoes several transcriptional and morphological changes that contribute to aberrant immunological responses, which is known as priming. Key molecules involved in the process, however, are not clearly defined. In the present study, we have demonstrated that level of microglial signal regulatory protein alpha (SIRP alpha) decreased during aging or inflammatory challenge. Functional studies suggested that downregulation of SIRP alpha released the brake of inflammatory response in microglia, revealing an inhibitory effect of SIRP alpha in microglial activation. Furthermore, we assessed the impact of SIRP alpha downregulation in PD pathogenesis using both cell culture and animal models. Our results showed that SIRP alpha deficiency resulted in abnormal inflammatory response and phagocytic activity of microglia, which in turn, further accelerated degeneration of dopaminergic neurons in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine or lipopolysaccharides mice models. These results collectively demonstrate that dysregulation of SIRP alpha signaling in microglia during aging plays a critical role in the pathogenesis of age-related neurological disorders such as PD.