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Caspase-2 activity modulates AMP receptor trafficking and dendritic spine dynamics. A soluble tau fragment generated by caspase-2 is elevated in Alzheimer's disease, Huntington's disease, and Lewy body disease and promotes cognitive defects. The genetic ablation of caspase-2 leads to symptomatic benefits in transgenic mice overexpressing mutant huntingtin or the amyloid-β precursor protein. Biallelic mutations in genes encoding p53-induced protein with a death domain 1, receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain cause intellectual, behavioral, and psychological abnormalities of varying severity, predominantly accompanied by pachygyria. Selective PIDDosome component inhibitors protect against neurotoxicity in in vitro models, which makes them promising therapeutic agents for the treatment of neurodegenerative diseases. The PIDDosome is a multiprotein complex that includes p53-induced protein with a death domain 1 (PIDD1), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and caspase-2, the activation of which is driven by PIDDosome assembly. In addition to the key role of the PIDDosome in the regulation of cell differentiation, tissue homeostasis, and organogenesis and regeneration, caspase-2, RAIDD and PIDD1 engagement in neuronal development was shown. Here, we focus on the involvement of PIDDosome components in neurodegenerative disorders, including retinal neuropathies, different types of brain damage, and Alzheimer's disease (AD), Huntington's disease (HD), and Lewy body disease. We also discuss pathogenic variants of PIDD1, RAIDD, and caspase-2 that are associated with intellectual, behavioral, and psychological abnormalities, together with prospective PIDDosome inhibition strategies and their potential clinical application. [ABSTRACT FROM AUTHOR]

Studies have shown that downregulation of nuclear-enriched autosomal transcript 1 (Neat1) may adversely affect the recovery of nerve function and the increased loss of hippocampal neurons in mice. Whether Neat1 has protective or inhibitory effects on neuronal cell apoptosis after secondary brain injury remains unclear. Therefore, the effects of Neat1 on neuronal apoptosis were observed. C57BL/6 primary neurons were obtained from the cortices of newborn mice and cultured in vitro, and an oxygen and glucose deprivation cell model was established to simulate the secondary brain injury that occurs after traumatic brain injury in vitro. The level of Neat1 expression in neuronal cells was regulated by constructing a recombinant adenovirus to infect neurons, and the effects of Neat1 expression on neuronal apoptosis after oxygen and glucose deprivation were observed. The experiment was divided into four groups: the control group, without any treatment, received normal culture; the oxygen and glucose deprivation group were subjected to the oxygen and glucose deprivation model protocol; the Neat1 overexpression and Neat1 downregulation groups were treated with Neat1 expression intervention techniques and were subjected to the in oxygen and glucose deprivation protocol. The protein expression levels of neurons p53-induced death domain protein 1 (PIDD1, a pro-apoptotic protein), caspase-2 (an apoptotic priming protein), cytochrome C (a pro-apoptotic protein), and cleaved caspase-3 (an apoptotic executive protein) were measured in each group using the western blot assay. To observe changes in the intracellular distribution of cytochrome C, the expression levels of cytochrome C in the cytoplasm and mitochondria of neurons from each group were detected by western blot assay. Differences in the cell viability and apoptosis rate between groups were detected by cell-counting kit 8 assay and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, respectively. The results showed that the apoptosis rate, PIDD1, caspase-2, and cleaved caspase-3 expression levels significantly decreased, and cell viability significantly improved in the Neat1 overexpression group compared with the oxygen and glucose deprivation group; however, Neat1 downregulation reversed these changes. Compared with the Neat1 downregulation group, the cytosolic cytochrome C level in the Neat1 overexpression group significantly decreased, and the mitochondrial cytochrome C level significantly increased. These data indicate that Neat1 upregulation can reduce the release of cytochrome C from the mitochondria to the cytoplasm by inhibiting the PIDD1-caspase-2 pathway, reducing the activation of caspase-3, and preventing neuronal apoptosis after oxygen and glucose deprivation, which might reduce secondary brain injury after traumatic brain injury. All experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China, on December 19, 2020 (approval No. 2020-895).

Parkinson’s disease (PD) is the second most neurodegenerative disease in the world. T cell infiltration in the central nervous system (CNS) has provided insights that the peripheral immune cells participate in the pathogenesis of PD. However, the association between the peripheral immune system and CNS remains to be elucidated. In this study, we analyzed incorporative substantia nigra (SN) expression data and blood expression data using the CIBERSORT to obtain the 22 immune cell fractions and then explored the molecular function to identify the potential key immune cell types and genes of PD. We observed that the proportions of naïve CD4 T cells, gamma delta T cells, resting natural killer (NK) cells, neutrophils in the blood, and regulatory T cells (Tregs) in the SN were significantly different between patients with PD and healthy controls (HCs). We identified p53-induced death domain protein 1 (PIDD1) as the hub gene of a PD-related module. The enrichment score of the neuron-specific gene set was significantly different between PD and HC, and genes in the neuron-related module were enriched in the biological process about mitochondria and synapses. These results suggested that the fractions of naïve CD4 T cells, gamma delta T cells, resting NK cells, and neutrophils may be used as a combined diagnostic marker in the blood, and Tregs in SN may be a potential therapeutic design target for PD.

Parkinson's disease (PD) is the second most neurodegenerative disease in the world. T cell infiltration in the central nervous system (CNS) has provided insights that the peripheral immune cells participate in the pathogenesis of PD. However, the association between the peripheral immune system and CNS remains to be elucidated. In this study, we analyzed incorporative substantia nigra (SN) expression data and blood expression data using the CIBERSORT to obtain the 22 immune cell fractions and then explored the molecular function to identify the potential key immune cell types and genes of PD. We observed that the proportions of naïve CD4 T cells, gamma delta T cells, resting natural killer (NK) cells, neutrophils in the blood, and regulatory T cells (Tregs) in the SN were significantly different between patients with PD and healthy controls (HCs). We identified p53-induced death domain protein 1 (PIDD1) as the hub gene of a PD-related module. The enrichment score of the neuron-specific gene set was significantly different between PD and HC, and genes in the neuron-related module were enriched in the biological process about mitochondria and synapses. These results suggested that the fractions of naïve CD4 T cells, gamma delta T cells, resting NK cells, and neutrophils may be used as a combined diagnostic marker in the blood, and Tregs in SN may be a potential therapeutic design target for PD. [ABSTRACT FROM AUTHOR]

Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi‐protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome‐induced p53‐activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro‐tumorigenic effect of PIDDosome‐mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence‐free survival in HCC patients. Synopsis: Hepatocyte ploidy is controlled by the PIDDosome and its loss causes increased hepatocyte ploidy, which protects mice from developing liver cancer. High tumor cell density, a surrogate of low ploidy, predicts poor recurrence free survival in HCC patients. The PIDDosome promotes DEN‐induced liver cancer in mice.Liver cancer arises preferentially from hepatocytes with low ploidy.Low tumor ploidy predicts poor recurrence‐free survival in HCC patients. [ABSTRACT FROM AUTHOR]

The PIDDosome is often used as the alias for a multi-protein complex that includes the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of an endopeptidase belonging to the caspase family, i.e. caspase-2. Yet, PIDD1 variants can also interact with a number of other proteins that include RIPK1 (also known as RIP1) and IKBKG (also known as NEMO), PCNA and RFC5, as well as nucleolar components such as NPM1 or NCL. This promiscuity in protein binding is facilitated mainly by autoprocessing of the full-length protein into various fragments that contain different structural domains. As a result, multiple responses can be mediated by protein complexes that contain a PIDD1 domain. This suggests that PIDD1 acts as an integrator for multiple types of stress that need instant attention. Examples are various types of DNA lesion but also the presence of extra centrosomes that can foster aneuploidy and, ultimately, promote DNA damage. Here, we review the role of PIDD1 in response to DNA damage and also highlight novel functions of PIDD1, such as in centrosome surveillance and scheduled polyploidisation as part of a cellular differentiation program during organogenesis. [ABSTRACT FROM AUTHOR]

Objective Bexarotene treatments exert neuroprotective effects on mice following traumatic brain injury (TBI). The present study aims to investigate the potential roles of the long noncoding RNA Neat1 in the neuroprotective effects of bexarotene. Materials and methods Adult male C57BL/6J mice (n = 80) and newborn mice (within 24 h after birth) (n = 20) were used to generate a “controlled cortical impact” (CCI) model and harvest primary cortex neurons, respectively. The HT22 cell line and the BV2 cell line were cultured under “normal” or “oxygen/glucose-deprived” (OGD) conditions. The relationship between RXR-α and the Neat1 promoter was clarified using ChIP-qPCR and dual-luciferase reporter gene assays. The mRNA alterations induced by Neat1 knockdown were measured using next-generation RNA sequencing. Proteins were captured by Neat1, pulled down and subjected to mass spectrometry. The neurological severity score, rotarod test and water maze test were employed to measure the animals’ motor and cognitive functions. Results Bexarotene prominently up-regulated the Neat1 level in an RXR-α-dependent manner. Neat1 knockdown induced significant changes in mRNA expression, and the altered mRNAs were involved in many biological processes, including synapse formation and axon guidance. In primary neurons, Neat1 knockdown inhibited and Neat1 over-expression prompted axon elongation. Multiple proteins, including Pidd1, were captured by Neat1. Neat1 inhibited cell apoptosis and restricted inflammation by capturing Pidd1. The in vitro anti-apoptotic and anti-inflammatory effects of Neat1 were further confirmed in C57BL/6 mice, which resulted in better motor and cognitive function after TBI. Conclusion Bexarotene up-regulates the lncRNA Neat1, which inhibits apoptosis and inflammation, thereby resulting in better functional recovery in mice after TBI. [ABSTRACT FROM AUTHOR]

Recent findings (Tsabar et al.) demonstrate that human cancer cells that evade the cell cycle blockage normally imposed by DNA damage experience sustained p53 signaling upon MDM2 degradation by caspase 2. Such a response may be connected to the delivery of immunostimulatory signals to ensure the elimination of genetically instable cancer cells. [ABSTRACT FROM AUTHOR]

Cells counter DNA damage through repair or apoptosis, yet a direct mechanism for this choice has remained elusive. When facing interstrand crosslinks (ICLs), the ICL-repair protein FANCI heterodimerizes with FANCD2 to initiate ICL excision. We found that FANCI alternatively interacts with a pro-apoptotic factor, PIDD1, to enable PIDDosome (PIDD1-RAIDD-caspase-2) formation and apoptotic death. FANCI switches from FANCD2/repair to PIDD1/apoptosis signaling in the event of ICL-repair failure. Specifically, removing key endonucleases downstream of FANCI/FANCD2, increasing ICL levels, or allowing damaged cells into mitosis (when repair is suppressed) all suffice for switching. Reciprocally, apoptosis-committed FANCI reverts from PIDD1 to FANCD2 after a failed attempt to assemble the PIDDosome. Monoubiquitination and deubiquitination at FANCI K523 impact interactor selection. These data unveil a repair-or-apoptosis switch in eukaryotes. Beyond ensuring the removal of unrepaired genomes, the switch's bidirectionality reveals that damaged cells can offset apoptotic defects via de novo attempts at lesion repair. [Display omitted] • FANCI binds either pro-repair FANCD2 or pro-apoptotic PIDD1 in response to ICLs • Interactor selection by FANCI is binary and regulated by deubiquitination • Repair failure triggers PIDD1 recruitment, PIDDosome formation, and apoptotic death • Apoptosis failure triggers reversal to FANCD2 and de novo attempts at ICL repair Shah et al. describe a mechanism by which cells decide their fate, repair or self-removal, after DNA damage. The mechanism relies on the ability of a DNA repair effector, FANCI, to engage an apoptotic device in a manner exclusive with its repair activity. [ABSTRACT FROM AUTHOR]

Cellular responses to stimuli can evolve over time, resulting in distinct early and late phases in response to a single signal. DNA damage induces a complex response that is largely orchestrated by the transcription factor p53, whose dynamics influence whether a damaged cell will arrest and repair the damage or will initiate cell death. How p53 responses and cellular outcomes evolve in the presence of continuous DNA damage remains unknown. Here, we have found that a subset of cells switches from oscillating to sustained p53 dynamics several days after undergoing damage. The switch results from cell cycle progression in the presence of damaged DNA, which activates the caspase-2-PIDDosome, a complex that stabilizes p53 by inactivating its negative regulator MDM2. This work defines a molecular pathway that is activated if the canonical checkpoints fail to halt mitosis in the presence of damaged DNA. • Post-irradiation, a subset of cells switches from oscillatory to sustained p53 levels • Switching is a late response that occurs more than 24 h following irradiation • Switching requires escape from irradiation-induced cell cycle arrest • The caspase-2-PIDDosome sustains p53 levels by degrading p53's inhibitor MDM2 Tsabar et al. show that a subset of cells switches from oscillatory to sustained p53 dynamics more than 24 h after irradiation-induced DNA damage. Switching is maximal at intermediate radiation doses, requires escape from irradiation-induced cell cycle arrest, and is facilitated by caspase-2-PIDDosome-mediated degradation of p53's inhibitor MDM2. [ABSTRACT FROM AUTHOR]