DJ-1, originally identified as an oncogene product, is a protein with various functions in cellular transformation, oxidative stress response, and transcriptional regulation. Although previous studies suggest that DJ-1 is cytoprotective, the mechanism by which DJ-1 exerts its survival functions remains largely unknown. Here we show that DJ-1 exerts its cytoprotection through inhibiting p53-Bax-caspase pathway. DJ-1 interacts with p53 in vitro and in vivo. Overexpression of DJ-1 decreases the expression of Bax and inhibits caspase activation, whereas knockdown of DJ-1 increases Bax protein levels and accelerates caspase-3 activation and cell death induced by UV exposure. Our data provide evidence that the protective effects of DJ-1 on apoptosis are associated with its ability of decreasing Bax level through inhibiting p53 transcriptional activity.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by selective loss of motor neurons in brain and spinal cord. TAR DNA-binding protein 43 (TDP-43) was identified as a major component of disease pathogenesis in ALS, frontotemporal lobar degeneration (FTLD), and other neurodegenerative disease. Despite the fact that TDP-43 is a multi-functional protein involved in RNA processing and a large number of TDP-43 RNA targets have been discovered, the initial toxic effect and the pathogenic mechanism underlying TDP-43-linked neurodegeneration remain elusive. In this study, we found that loss of TDP-43 strongly induced a nuclear translocation of TFEB, the master regulator of lysosomal biogenesis and autophagy, through targeting the mTORC1 key component raptor. This regulation in turn enhanced global gene expressions in the autophagy-lysosome pathway (ALP) and increased autophagosomal and lysosomal biogenesis. However, loss of TDP-43 also impaired the fusion of autophagosomes with lysosomes through dynactin 1 downregulation, leading to accumulation of immature autophagic vesicles and overwhelmed ALP function. Importantly, inhibition of mTORC1 signaling by rapamycin treatment aggravated the neurodegenerative phenotype in a TDP-43-depleted Drosophila model, whereas activation of mTORC1 signaling by PA treatment ameliorated the neurodegenerative phenotype. Taken together, our data indicate that impaired mTORC1 signaling and influenced ALP may contribute to TDP-43-mediated neurodegeneration.

Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.

Omi, also known as high temperature requirement factor A2 (HtrA2), is a serine protease that was originally identified as a proapoptotic protein. Like Smac/Diablo, it antagonizes inhibitor of apoptosis proteins when released into the cytosol on apoptotic stimulation. Loss of its protease activity in mnd2 (motor neuron degeneration 2) mice is associated with neurodegeneration. However, the detailed mechanisms by which Omi regulates the pathogenesis of neurodegenerative disease remain largely unknown. We report here that Omi participates in the pivotal cellular degradation process known as autophagy. It activates autophagy through digestion of Hax-1, a Bcl-2 family-related protein that represses autophagy in a Beclin-1 (mammalian homologue of yeast ATG6)-dependent pathway. Moreover, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T a-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Knockdown of Omi decreases the basal level of autophagy and increases the level of the above target proteins. Furthermore, S276C Omi, the protease-defective mutant found in mnd2 mice, fails to regulate autophagy. Increased autophagy substrates and the formation of aggregate structures are observed in the brains of mnd2 mice. These results identify Omi as a novel regulator of autophagy and suggest that Omi might be important in the cellular quality control of proteins involved in neurodegenerative diseases.

No abstract

REV-ERBα, the NR1D1 (nuclear receptor subfamily 1, group D, member 1) gene product, is a dominant transcriptional silencer that represses the expression of genes involved in numerous physiological functions, including circadian rhythm, inflammation, and metabolism, and plays a crucial role in maintaining immune functions. Microglia-mediated neuroinflammation is tightly associated with various neurodegenerative diseases and psychiatric disorders. However, the role of REV-ERBα in neuroinflammation is largely unclear. In this study, we investigated whether and how pharmacological activation of REV-ERBα affected lipopolysaccharide (LPS)-induced neuroinflammation in mouse microglia in vitro and in vivo. In BV2 cells or primary mouse cultured microglia, application of REV-ERBα agonist GSK4112 or SR9011 dose-dependently suppressed LPS-induced microglial activation through the nuclear factor kappa B (NF-κB) pathway. In BV2 cells, pretreatment with GSK4112 inhibited LPS-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα) kinase (IκK), thus restraining the phosphorylation and degradation of IκBα, and blocked the nuclear translocation of p65, a NF-κB subunit, thereby suppressing the expression and secretion of the proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα). Moreover, REV-ERBα agonist-induced inhibition on neuroinflammation protected neurons from microglial activation-induced damage, which were also demonstrated in mice with their ventral midbrain microinjected with GSK4112, and then stimulated with LPS. Our results reveal that enhanced REV-ERBα activity suppresses microglial activation through the NF-κB pathway in the central nervous system.

Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.

Background: DJ-1 is a protein in association with Parkinson disease and tumorigenesis. Results: DJ-1 increases its mitochondrial distribution in response to ultraviolet B (UVB) irradiation and binds to Bcl-XL in an oxidation-dependent manner to prevent Bcl-XL degradation. Conclusion: Bcl-XL is a new partner of DJ-1 in mitochondria and DJ-1 stabilizes Bcl-XL in response to UVB irradiation. Significance: DJ-1 plays important roles in mitochondria by regulating Bcl-XL functions.