Mutations in PINK1 (PTEN-induced putative kinase 1) cause early onset familial Parkinson's disease (PD). PINK1 accumulates on the outer membrane of damaged mitochondria followed by recruiting parkin to promote mitophagy. Here, we demonstrate that BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a mitochondrial BH3-only protein, interacts with PINK1 to promote the accumulation of full-length PINK1 on the outer membrane of mitochondria, which facilitates parkin recruitment and PINK1/parkin-mediated mitophagy. Inactivation of BNIP3 in mammalian cells promotes PINK1 proteolytic processing and suppresses PINK1/parkin-mediated mitophagy. Hypoxia-induced BNIP3 expression results in increased expression of full-length PINK1 and mitophagy. Consistently, expression of BNIP3 in Drosophila suppresses muscle degeneration and the mitochondrial abnormality caused by PINK1 inactivation. Together, the results suggest that BNIP3 plays a vital role in regulating PINK1 mitochondrial outer membrane localization, the proteolytic process of PINK1 and PINK1/parkin-mediated mitophagy under physiological conditions. Functional up-regulation of BNIP3 may represent a novel therapeutic strategy to suppress the progression of PD.
Mutations in the ATP13A2 gene are associated with KuforRakeb syndrome (KRS) and are found also in patients with various other types of parkinsonism. ATP13A2 encodes a predicted lysosomal P5-type ATPase that plays important roles in regulating cation homeostasis. Disturbance of cation homeostasis in brains is indicated in Parkinson disease pathogenesis. In this study, we explored the biological function of ATP13A2 as well as the pathogenic mechanism of KRS pathogenic ATP13A2 mutants. The results revealed that wild-type ATP13A2, but not the KRS pathogenic ATP13A2 mutants, protected cells from Mn 2؉ -induced cell death in mammalian cell lines and primary rat neuronal cultures. In addition, wild-type ATP13A2 reduced intracellular manganese concentrations and prevented cytochrome c release from mitochondria compared with the pathogenic mutants. Furthermore, endogenous ATP13A2 was up-regulated upon Mn 2؉ treatment. Our results suggest that ATP13A2 plays important roles in protecting cells against manganese cytotoxicity via regulating intracellular manganese homeostasis. The study provides a potential mechanism of KRS and parkinsonism pathogenesis.Mutations in ATP13A2 were initially identified in patients with Kufor-Rakeb syndrome (KRS), 2 an atypical form of inherited parkinsonism. KRS is characterized by juvenile-onset autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration with clinical features of Parkinson disease (PD) plus spasticity, supranuclear upgaze paresis, and dementia (1). Homozygous and heterozygous mutations in ATP13A2 are also found in patients with various parkinsonism, including juvenile parkinsonism, young-onset PD, early-onset PD, and familial PD (2-9). ATP13A2 encodes a predicted lysosomal P5-type cationtransporting ATPase with multiple transmembrane domains. It is highly expressed in the brain, especially in the substantia nigra, the region with characteristic dopaminergic neuronal loss in PD. Ypk9, a yeast ortholog of ATP13A2, was shown to function as a manganese transporter to protect cells from excess Mn 2ϩ exposure, whereas loss of Ypk9 increases the sensitivity of yeast to Mn 2ϩ toxicity (10, 11). Previous studies have suggested that cation disturbance is involved in pathogenesis of PD neurodegeneration. Increased levels of cations, including iron and aluminum, are found in the substantial nigra of the PD patient brain (12, 13). Chronic occupational exposure to copper and/or manganese is associated with higher incidence of PD in a case-control study (14). Furthermore, excess levels of Mn 2ϩ accumulation in brains associated with occupational exposure, psychostimulant drug abuse, and liver disease result in an atypical form of parkinsonism in human (15).PD and parkinsonism are believed to be consequences of interactions between both genetic and environmental components (16,17). In this study, we aimed to explore the connection between the KRS-associated ATP13A2 genetic defect and manganese-associated toxicity. Our results show that wild-type ATP13A2 (ATP13A2WT), but not KRS-as...
Epidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through activation of epidermal TLR4/IL-36R crosstalk. This activation is dependent upon NETs formation and integrity, as targeting NETs with DNase I or CI-amidine in vivo improves disease in the imiquimod (IMQ)-induced psoriasis-like mouse model, decreasing IL-17A, lipocalin2 (LCN2), and IL-36G expression. Proinflammatory activity of NETs, and LCN2 induction, is dependent upon activation of TLR4/IL-36R crosstalk and MyD88/nuclear factor-kappa B (NF-κB) down-stream signaling, but independent of TLR7 or TLR9. Notably, both TLR4 inhibition and LCN2 neutralization alleviate psoriasis-like inflammation and NETs formation in both the IMQ model and K14-VEGF transgenic mice. In summary, these results outline the mechanisms for the proinflammatory activity of NETs in skin and identify NETs/TLR4 as novel therapeutic targets in psoriasis.
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