Loss of PINK1 inhibits apoptosis by upregulating α-synuclein in inflammation-sensitized hypoxic-ischemic injury in the immature brains.

The incidence of preterm birth is rising worldwide. Among preterm infants, many face a lifetime of neurologic impairments. Recent studies have revealed that systemic inflammation can sensitize the immature brain to hypoxic-ischemic (HI) injury. Therefore, it is important to identify the mechanisms involved in inflammation-sensitized HI injury in immature brains. PTEN-induced putative kinase 1 (PINK1) is a regulatory protein that is highly expressed in the brain. We have previously found that PINK1 gene knockout can protect matured brains from HI injury in postnatal day 10 mice. However, the mechanisms are unknown. In this study, we employed an inflammation-sensitized HI injury model using postnatal day 3 mice to study the roles and mechanisms that PINK1 plays in the immature brains. Lipopolysaccharide (LPS) was injected intraperitoneally into the mice before HI treatment to set up the model. We found that PINK1-knockout mice had fewer brain infarcts and less cell apoptosis than did the wild-type mice. Furthermore, we found that α-synuclein was markedly higher in the PINK1-knockout mice than in the wild-type mice, and inhibition of α-synuclein through small interfering RNA (siRNA) reversed the protective effect in the PINK1-knockout mice. Collectively, these findings indicate that loss of PINK1 plays a novel role in the protection of inflammation-sensitized HI brain damage.