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Lin, Rong-Rong, Qing-Qing Tao, and Zhi-Ying Wu. "Early-Onset Parkinson’s Disease and Brain Iron Accumulation Caused by a Novel Homozygous DJ-1 Mutation." Journal of Parkinson's Disease 12, no. 3 (April 5, 2022): 813–19. http://dx.doi.org/10.3233/jpd-213033.
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DJ-1 mutations are rare causes of autosomal recessive early-onset Parkinson’s disease (AR-EOPD) and relatively rarely reported in the Chinese population. Here, we used the whole-exome sequencing and Sanger sequencing to investigate DJ-1 mutations in the Chinese population and confirmed the pathogenicity of the mutation using primary fibroblasts established from skin biopsies. We identified a novel homozygous mutation (c.390delA, p.D131Tfs*3) in DJ-1 in a consanguineous Chinese family. The proband in this family had parkinsonism at the age of 22. His brain MRI indicated brain iron accumulation in the basal ganglia and cerebellum. The novel mutation caused DJ-1 protein deficiency, led to mitochondrial dysfunction, inhibited cell proliferation, and anti-oxidant defense.
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Qin, Li-xia, Jie-qiong Tan, Hai-nan Zhang, Kousar Rizwana, Jia-hong Lu, Jian-guang Tang, Bo Jiang, et al. "BAG5 Interacts with DJ-1 and Inhibits the Neuroprotective Effects of DJ-1 to Combat Mitochondrial Oxidative Damage." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/5094934.
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Loss-of-function mutations in gene encoding DJ-1 contribute to the pathogenesis of autosomal recessive early-onset familial forms of Parkinson’s disease (PD). DJ-1 is a multifunctional protein and plays a protective role against oxidative stress-induced mitochondrial damage and cell death, but the exact mechanism underlying this is not yet clearly understood. Here, using coimmunoprecipitation (Co-IP) and immunofluorescence methods, we prove that Bcl-2-associated athanogene 5 (BAG5), a BAG family member, interacts with DJ-1 in mammalian cells. Moreover, we show that BAG5 could decrease stability of DJ-1 and weaken its role in mitochondrial protection probably by influencing dimerization in stress condition. Our study reveals the relationship of BAG5 and DJ-1 suggesting a potential role for BAG5 in the pathogenesis of PD through its functional interactions with DJ-1.
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Lewandowska, Aleksandra, Trung Nghia Vo, Thuy-Dung Ho Nguyen, Khadija Wahni, Didier Vertommen, Frank Van Breusegem, David Young, and Joris Messens. "Bifunctional Chloroplastic DJ-1B from Arabidopsis thaliana is an Oxidation-Robust Holdase and a Glyoxalase Sensitive to H2O2." Antioxidants 8, no. 1 (January 1, 2019): 8. http://dx.doi.org/10.3390/antiox8010008.
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Members of the DJ-1 protein family are multifunctional enzymes whose loss increases the susceptibility of the cell to oxidative stress. However, little is known about the function of the plant DJ-1 homologs. Therefore, we analyzed the effect of oxidation on the structure and function of chloroplastic AtDJ-1B and studied the phenotype of T-DNA lines lacking the protein. In vitro oxidation of AtDJ-1B with H2O2 lowers its glyoxalase activity, but has no effect on its holdase chaperone function. Remarkably, upon oxidation, the thermostability of AtDJ-1B increases with no significant alteration of the overall secondary structure. Moreover, we found that AtDJ-1B transcript levels are invariable, and loss of AtDJ-1B does not affect plant viability, growth and stress response. All in all, two discrete functions of AtDJ-1B respond differently to H2O2, and AtDJ-1B is not essential for plant development under stress.
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Kolisek, Martin, Augusto C. Montezano, Gerhard Sponder, Aikaterini Anagnostopoulou, Juergen Vormann, Rhian M. Touyz, and Joerg R. Aschenbach. "PARK7/DJ-1 dysregulation by oxidative stress leads to magnesium deficiency: implications in degenerative and chronic diseases." Clinical Science 129, no. 12 (October 30, 2015): 1143–50. http://dx.doi.org/10.1042/cs20150355.
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Disturbed magnesium (Mg2+) homoeostasis and increased levels of OS (oxidative stress) are associated with poor clinical outcomes in patients suffering from neurodegenerative, cardiovascular and metabolic diseases. Data from clinical and animal studies suggest that MD (Mg2+ deficiency) is correlated with increased production of ROS (reactive oxygen species) in cells, but a straightforward causal relationship (including molecular mechanisms) between the two conditions is lacking. The multifactorial protein PARK7/DJ-1 is a major antioxidant protein, playing a key role in cellular redox homoeostasis, and is a positive regulator of AR (androgen receptor)-dependent transcription. SLC41A1 (solute carrier family 41 member 1), the gene encoding a ubiquitous cellular Mg2+E (Mg2+efflux) system, has been shown to be regulated by activated AR. We hypothesize that overexpression/up-regulation of PARK7/DJ-1, attributable to OS and related activation of AR, is an important event regulating the expression of SLC41A1 and consequently, modulating the Mg2+E capacity. This would involve changes in the transcriptional activity of PARK7/DJ-1, AR and SLC41A1, which may serve as biomarkers of intracellular MD and may have clinical relevance. Imipramine, in use as an antidepressant, has been shown to reduce the Mg2+E activity of SLC41A1 and OS. We therefore hypothesize further that administration of imipramine or related drugs will be beneficial in MD- and OS-associated diseases, especially when combined with Mg2+ supplementation. If proved true, the OS-responsive functional axis, PARK7/DJ-1–AR–SLC41A1, may be a putative mechanism underlying intracellular MD secondary to OS caused by pro-oxidative stimuli, including extracellular MD. Furthermore, it will advance our understanding of the link between OS and MD.
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Melvin, Prasad, Kondalarao Bankapalli, Patrick D’Silva, and P. V. Shivaprasad. "Methylglyoxal detoxification by a DJ-1 family protein provides dual abiotic and biotic stress tolerance in transgenic plants." Plant Molecular Biology 94, no. 4-5 (April 25, 2017): 381–97. http://dx.doi.org/10.1007/s11103-017-0613-9.
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Ross, O. A., and M. J. Farrer. "Pathophysiology, pleotrophy and paradigm shifts: genetic lessons from Parkinson's disease." Biochemical Society Transactions 33, no. 4 (August 1, 2005): 586–90. http://dx.doi.org/10.1042/bst0330586.
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PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including α-synuclein, parkin, ubiquitin C-ter-minal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable α-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.
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Bankapalli, Kondalarao, SreeDivya Saladi, Sahezeel S. Awadia, Arvind Vittal Goswami, Madhuja Samaddar, and Patrick D'Silva. "Robust Glyoxalase activity of Hsp31, a ThiJ/DJ-1/PfpI Family Member Protein, Is Critical for Oxidative Stress Resistance inSaccharomyces cerevisiae." Journal of Biological Chemistry 290, no. 44 (September 14, 2015): 26491–507. http://dx.doi.org/10.1074/jbc.m115.673624.
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Yang, Xinglong, and Yanming Xu. "Mutations in theATP13A2Gene and Parkinsonism: A Preliminary Review." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/371256.
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Parkinson’s disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genesParkin, Pink1, DJ-1, ATP13A2, PLA2G6, andFBXO7have been linked to PD susceptibility. Such mutations inATP13A2, also namedPARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about theATP13A2gene, clinical characteristics of patients with PD-associatedATP13A2mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibitingα-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss anotherATP13A2mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway wherebyATP13A2mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets.
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Liu, Tsai-Wei, Chiung-Mei Chen, and Kuo-Hsuan Chang. "Biomarker of Neuroinflammation in Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 8 (April 8, 2022): 4148. http://dx.doi.org/10.3390/ijms23084148.
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Parkinson’s disease (PD) is caused by abnormal accumulation of α-synuclein in dopaminergic neurons of the substantia nigra, which subsequently causes motor symptoms. Neuroinflammation plays a vital role in the pathogenesis of neurodegeneration in PD. This neuroinflammatory neurodegeneration involves the activation of microglia, upregulation of proinflammatory factors, and gut microbiota. In this review, we summarized the recent findings on detection of PD by using inflammatory biomarkers, such as interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor (TNF)-α; regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and high-sensitivity c-reactive protein (hsCRP); and radiotracers such as [11C]PK11195 and [18F]-FEPPA, as well as by monitoring disease progression and the treatment response. Many PD-causing mutations in SNCA, LRRK2, PRKN, PINK1, and DJ-1 are also associated with neuroinflammation. Several anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAID), inhibitors of TNF-α and NLR family pyrin domain containing 3 (NLRP3), agonists of nuclear factor erythroid 2-related factor 2 (NRF2), peroxisome proliferator-activated receptor gamma (PPAR-γ), and steroids, have demonstrated neuroprotective effects in in vivo or in vitro PD models. Clinical trials applying objective biomarkers are required to investigate the therapeutic potential of anti-inflammatory medications for PD.
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Ohnishi, Y., and S. Horinouchi. "The A-factor regulatory cascade that leads to morphological development and secondary metabolism in Streptomyces." Biofilms 1, no. 4 (October 2004): 319–28. http://dx.doi.org/10.1017/s1479050504001462.
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A-factor (2-isocapryloyl-3R-hydroxymethyl-γ-butyrolactone) is a chemical signalling molecule, or microbial hormone, that triggers aerial mycelium formation and secondary metabolism in Streptomyces griseus. A-factor pro- duced in a growth-dependent manner switches on the transcription of adpA, encoding a transcriptional activator, by binding to ArpA, the A-factor receptor protein, which has bound to the adpA promoter, and dissociating the bound ArpA from the DNA. AdpA then activates a number of genes of various functions required for morphological development and secondary metabolism, forming an AdpA regulon. ArpA, which belongs to the TetR family, contains a helix–turn–helix DNA-binding motif in its N-terminal portion and an A-factor-binding pocket (5 Å (0.5 nm) diameter and 20 Å (2 nm) long) in its C-terminal portion, as implied by X-ray crystallography of CprB, an ArpA homologue. The ligand pocket, which can accommodate an entire A-factor-type molecule of γ-butyrolactone, is completely embedded in the C-terminal portion. Upon binding A-factor, a long helix connecting the A-factor-binding and ligand-binding domains is relocated, as a result of which the DNA-binding helix moves outside, resulting in dissociation from DNA. AdpA, which belongs to the AraC/XylS family, contains a ThiJ/PfpI/DJ-1-like dimerization domain in its N-terminal portion and an AraC/XylS-type DNA-binding domain in its C-terminal portion. For transcriptional activation, AdpA can bind to various positions with respect to the transcriptional start points of the target genes and sometimes to multiple sites. We show here how A-factor triggers secondary metabolism and morphological development in S. griseus, with emphasis on the two key transcriptional factors, ArpA and AdpA, in the A-factor regulatory cascade.
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Golos, Aleksandra, Dorota Jesionek-Kupnicka, Tadeusz Robak, Ewa Wawrzyniak, Lidia Anna Gil, Mieczyslaw Komarnicki, Anna Wache, and Agnieszka Wierzbowska. "The Role of the Slit-Robo Family in Adult Patients with Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 3816. http://dx.doi.org/10.1182/blood.v126.23.3816.3816.
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Abstract Introduction: SLIT-ROBO is newly discovered ligand-receptor family of neuronal guidance molecules. Recently, it has been proved that these proteins are involved in both, physiologic and pathologic angiogenesis. In animal models, it was shown both, pro-and antiangiogenic of SLIT-ROBO signaling. Moreover, the interaction of SLIT ligands with their roundabout receptors (ROBO) results in promotion of apoptosis, adhesion and blocking of cell cycle. There is evidence that SLIT-ROBO proteins are involved in pathogenesis of solid tumors, both in angiogenesis dependent and independent way. The role of SLIT-ROBO proteins in biology of acute myeloid leukemia (AML) remains unknown.The only two hitherto published studies considering ROBO4 expression in AML have revealed its increased expression in the blasts cells. The aim of the study was to evaluate the role of SLIT-ROBO proteins in AML. The expression of SLIT ligands, and their receptors ROBO was assessed in bone marrow of newly diagnosed AML patients and in the control group. The expression level of the proteins was correlated with known prognostic factors, response to treatment and overall survival (OS), as well as angiogenesis activity. To our knowledge, it has been the first study investigating the whole family of SLIT-ROBO proteins in AML. Methods: Expression SLIT-ROBO proteins was assessed in bone marrow biopsy specimens of 79 newly diagnosed AML patients with median age 59 years [18-87]. The paraffin-embedded tissue blocks were retrieved and subjected to immunohistochemistry for SLIT ligands (SLIT1, SLIT2, SLIT3), and their receptors ROBO1, ROBO2, ROBO3, and ROBO4. The positive blasts cells were semi-quantitatively analyzed according to previously published methods (Perrone et al, 2006). For the purpose of analysis the patients were divided into "low-expressers" and "high-expressers". Concurrently, all samples were immunostained for CD34 to calculate microvessel density (MVD) as an equivalent of angiogenesis. The control group was composed of 23 BM biopsies form patients with newly diagnosed lymphoma without bone marrow involvement. Results: Expression of ROBO receptors and SLIT ligands in AML patients and in the control group. In our study higher expression of ROBO1, ROBO2, and ROBO3 was observed more often in AML patients compared to the control group (p<0.0001, p<0.001, and p=0.09, respectively, Fig 1.). In contrast, low expression of SLIT1, SLIT2, and SLIT3 ligands has been shown more often in AML than in control BM samples (p<0.0001, p=0.003, and p=0.001, respectively,Fig.2.). Higher expression of ROBO1, ROBO2, and ROBO3 was more often in AML patients ≥60 years (p=0.04, p=0.008, and p=0.02, respectively).Conversely, low expression of ROBO4 was more often observed in elderly AML (p=0.06). The majority of patients with de novo AML had low expression of SLIT1 and SLIT2 (p=0.053 and p=0.055, respectively). As to ROBO, higher expression of ROBO2 in the group with secondary AML was more frequent (p=0.09). No significant correlations between the SLIT-ROBO proteins' expression,neither cytogenetic risk group nor clinical stage parameters such as WBC, hemoglobin level, proportion of leukemic blasts in BM, or LDH activity were found. Similarly, neither of the SLIT-ROBO proteins influenced the complete remission rate (CR) and overall survival (OS). Relationship between SLIT-ROBO expression and angiogenesis activity in AML patients and control group. Significantly higher MVD in BM of AML patients than in control group (Me 51 [9-140] vs 16 [4-78], p<0.0001) has been observed. ROBO4was the only protein that expression correlated significantly with MVD. Higher expression of ROBO4 was associated with higher MVD in both, AML and the control group (p=0.05 and p=0.01, respectively). Conclusions: SLIT-ROBO family members play a role in biology of AML. ROBO4 is involved in both, physiologic and pathologic angiogenesis A better understanding of SLIT-ROBO signaling pathway in leukemic blasts may create new optionsfor AML therapy. Acknowledgments: AG and DJ-K both equally contributed to the study. This work was supported by grants from Medical University of Lodz, Lodz, Poland (502-03/1-093-01/502-14-077 and 503/1-093-01/503-11-001). Disclosures Robak: Eisai Inc: Research Funding. Wierzbowska:Janssen, Celgene: Consultancy.
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Zheng, Wei, Xiao Han, Bing Han, Gang Li, Jing Gan, Tian Wang, Bo Xu, et al. "LAR Downregulation Protects the Astrocytic U251 and Cocultured SH-SY5Y Cells in a Rotenone-Induced Parkinson’s Disease Cell Model." International Journal of Molecular Sciences 24, no. 13 (July 5, 2023): 11111. http://dx.doi.org/10.3390/ijms241311111.
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Leukocyte common antigen-related protein tyrosine phosphatase (LAR) is a member of the protein tyrosine phosphatase family that serves as a key regulator of cellular survival. It is also involved in neurodevelopment and brain disorders. This study was designed to investigate the role of LAR in a cell-based model of Parkinson’s disease (PD) in which U251 and SH-SY5Y cells were used as models of astrocytes and dopaminergic neurons, respectively. Cell viability, cell death, cell morphology, protein phosphorylation and expression, ATP levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential were analyzed in the wild-type (WT) and heterozygous LAR-knockout astrocytoma U251 cells to assess the cell state, signal transduction, and mitochondrial function. LAR downregulation showed a protective effect in rotenone-exposed U251 cells by increasing cell viability, reducing cell mortality, and restoring appropriate cellular morphology. LAR downregulation enhanced IGF-1R phosphorylation and downstream signal transduction as evidenced by increases in the Akt and GSK-3β phosphorylation, as well as the upregulation of NRF2 and HO-1. The downregulation of LAR also augmented DJ-1 levels in these cells. The enhanced Akt and GSK-3β phosphorylation contributed to a reduced Bax/Bcl2 ratio and suppressed apoptosis after rotenone exposure. Heterozygous LAR-knockout U251 cells exhibited higher mitochondrial function evidenced by increased mitochondrial membrane potential, ATP contents, and reduced ROS production compared to the WT cells following rotenone exposure. Further studies showed that the astrocytic protection mediated by the heterozygous knockout of LAR was associated with the activation of Akt. A specific Akt inhibitor, MK2206, reduced the cell viability, Akt and GSK3β phosphorylation, and HO-1 and NRF2 expression in U251 cells exposed to rotenone. Astrocytes provide structural and metabolic support to maintain neuronal health. Astrocytic glial cell-derived neurotrophic factor (GDNF) production is vital for dopaminergic neuron survival. Heterozygous LAR-knockout U251 cells produced higher amounts of GDNF than the WT cells. The SH-SY5Y cells cocultured with heterozygous LAR-knockout U251 cells exhibited greater viability than that of cells cocultured with WT U251 cells in response to rotenone. Together, these findings demonstrate that the heterozygous knockout of LAR in astrocytes can play a key role in protecting both astrocytic cells and cocultured neurons in a rotenone-induced cell-based model of PD. This neuroprotective effect is attributable to the augmentation of IGF1R-Akt-GDNF signaling and the maintenance of astrocytic mitochondrial function.
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Oduro, Jennifer, Ronald Simon, Natalia Gorbokon, Christoph Fraune, Julia Bluhm, Vivian Scheuplein, Elisa Kieback, Matthias Obenaus, Thomas Blankenstein, and Eugen Leo. "95 MAGE-A1 protein expression pattern in > 5,000 tumor and healthy tissue samples: Validation of MAGE-A1 as an ideal target for TCR-based cell therapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A104. http://dx.doi.org/10.1136/jitc-2021-sitc2021.095.
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BackgroundCancer testis antigens (CTAs) are considered attractive targets for T cell receptor (TCR)-based cellular therapies as their expression in healthy adults is considered restricted to the immune-privileged testis. However, low-level expression of some CTAs in healthy tissue has been observed, resulting in significant on-target/off-cancer toxicity. Melanoma associated antigen 1 (MAGE-A1) is a member of the MAGE-A CTA family, whose members are known to influence cellular signaling pathways through their E3 ubiquitin ligase-binding MAGE homology domain. MAGE-A proteins are frequently expressed in different cancer types, have been linked to oncogenic activity and their expression has been associated with poor prognosis.1 Literature data suggest that in healthy tissues MAGE-A1 is detected in testis, only, with one exception suggesting MAGE-A1 RNA expression in cerebellum and cerebrum.2 Therefore, to evaluate MAGE-A1 as a potential target for cellular immunotherapies, an in-depth analysis of MAGE-A1 expression in > 70 different healthy tissue types and > 5,000 cancer biopsies was conducted, aiming to assess if MAGE-A1 represents a valid and safe target.MethodsA MAGE-A1 antibody with high specificity (TK-AbMA1P) was identified and characterized for immunohistochemistry. A large panel of > 70 different healthy tissue types and > 5,000 tumor biopsies was explored and scored for MAGE-A1 expression by tissue microarray. Identified cancer entities with relevant MAGE-A1 expression were further investigated to assess spatial intratumoral MAGE-A1 expression distribution and expression consistency between primary tumor and lymph node/distant metastases.ResultsCharacterization of TK-AbMA1P demonstrated fully paralog-selective staining for MAGE-A1. Analysis of MAGE-A1 expression in over 70 different healthy tissues confirmed strictly selective expression of MAGE-A1 in testis. An extended analysis of various CNS tissues including cerebellum and cerebrum did not reveal any expression in CNS. The analysis of > 5,000 tumor biopsies showed significant MAGE-A1 expression in distinct subgroups of multiple major tumor types with high unmet medical need. Substantial expression was detected for example in non-small-cell lung cancer, various breast cancer subtypes, gastrointestinal and urogenital cancers, among others. Extended analysis of the MAGE-A1 positive tumors demonstrated highly homogenous and consistent spatial intratumoral distribution of MAGE-A1 expression as well as between primary tumor and metastases.ConclusionsThis analysis confirms that MAGE-A1 is a highly selectively expressed CTA and demonstrates relevant expression in various indications with high unmet medical need, suggesting that MAGE-A1 is an ideal target for highly potent TCR-based adoptive cell therapy.ReferencesWeon JL, Potts PR. The MAGE protein family and cancer. Curr Opin Cell Biol 2015;37:1–8.Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM, Phan GQ, Hughes MS, Kammula US, Miller AD, Hessman CJ, Stewart AA, Restifo NP, Quezado MM, Alimchandani M, Rosenberg AZ, Nath A, Wang T, Bielekova B, Wuest SC, Akula N, McMahon FJ, Wilde S, Mosetter B, Schendel DJ, Laurencot CM, Rosenberg SA. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013;36(2):133–51.Ethics ApprovalThis study was approved by the Ethics Commission of the Ärztekammer Hamburg; approval number WF-049/09. Participants gave informed consent before taking part.
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Yabe, Ichiro, Yuka Hamaya, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Mamiko Anada, Hideaki Miyoshi, and Tatsuya Atsumi. "ODP285 A Case of Encephalitis and Adrenal Insufficiency in a Patient With Panhypopituitarism After COVID-19 Vaccination." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A479—A480. http://dx.doi.org/10.1210/jendso/bvac150.996.
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Abstract Background Since COVID-19 vaccination was introduced, various adverse effects have been linked to the vaccines. In patients with hypopituitarism, adrenal insufficiency due to the side reactions including fever of COVID-19 vaccination is concerned. Clinical Case A 33-year woman was on medical therapy including hydrocortisone (HC) for panhypopituitarism arising from surgical treatment of a pituitary adenoma in 2006. She received a COVID-19 vaccination on day X-3. On day X-2, she developed fever in the morning and became unconscious in the evening. She was brought to our hospital by her family at night on day X. She had fever of 40.5°C, low blood pressure, and Glasgow Coma Scale (GCS) of 11. Her neck was supple and she had no quadriplegia. A COVID-19 PCR test was negative. Blood tests showed elevated white blood cell count (8900/μL; reference range: 3300–8600/µL) and C-reactive protein (138.3 mg/l; reference range: 0-1.44 mg/l). Blood glucose (81 mg/dL), ACTH (<3. 00 pg/mL; reference range: 7.2–63.3 pg/mL), and cortisol (1.9 μg/dL; reference range: 2.9–19.4 µg/dL) were low. Serum electrolytes were normal. A computed tomography scan showed no abnormality. Adrenal insufficiency was suspected, and she received HC intravenously. Her blood glucose and blood pressure increased, but her disorientation persisted. Lumbar puncture with cerebrospinal fluid (CSF) examination revealed slightly elevated cell counts (8 μ/L; reference range ≤4 μ/L) with average protein and glucose levels. Magnetic resonance imaging (MRI) of the brain revealed abnormal hyperintensity in the splenium of the corpus callosum on diffusion-weighted images and decreased apparent diffusion coefficient in the lesion, suggesting clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). During her hospital stay, she received a 7-day course of meropenem and acyclovir for suspected meningoencephalitis. Her consciousness disturbance improved to GCS of 15 on day X+1 and her fever decreased on day X+2. HSV and VZV PCR tests were negative on CSF examination, and antibiotics and antivirals were discontinued on day X+7. On day X+8, brain MRI showed complete resolution of the corpus callosum lesion. She discharged on day X+18 without any neurological sequelae. Conclusions For most vaccines, the incidence rates of encephalitis are low at 0.1–0.2 per 100,000 vaccinated individuals (1). The present patient developed fever and adrenal insufficiency after COVID-19 vaccination, and her prolonged disturbance of consciousness after HC administration led to the diagnosis of MERS. MERS should be considered in patients with adrenocortical insufficiency who show delayed recovery from unconsciousness with HC administration after COVID-19 vaccination. Reference: (1) Huynh W, Cordato DJ, Kehdi E, Masters LT, Dedousis C. Post-vaccination encephalomyelitis: literature review and illustrative case. J Clin Neurosci. 2008 Dec;15(12): 1315-22. Presentation: No date and time listed
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Riabov, Vladimir, Qingyu Xu, Nanni Schmitt, Alexander Streuer, Johann-Christoph Jann, Alina Wein, Eva Altrock, et al. "Preclinical Assessment of Alvocidib in Combination with 5-Azacytidine in High-Risk Myelodysplastic Syndromes." Blood 138, Supplement 1 (November 5, 2021): 4649. http://dx.doi.org/10.1182/blood-2021-150778.
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Abstract Hypomethylating therapy with 5-azacytidine (5-Aza) is a standard-of-care for patients with higher-risk myelodysplastic syndromes (MDS). Response is induced in approximately 50% of 5-Aza treated patients. However, despite robust efficacy in responders, relapse is almost certain. Recently, inhibitors of anti-apoptotic BCL-2 protein family members have shown potent activity against AML and higher-risk MDS in combination with 5-Aza. Alvocidib (Alv), a cyclin-dependent kinase 9 inhibitor and indirect transcriptional repressor of the anti-apoptotic BCL-2 family member MCL-1, has shown anti-leukemic effects in combination with 5-Aza in a phase 1 study of AML (Lee DJ et al, Expert Opin Investig Drugs 2019; Zeidner JF et al, Leuk Res 2015). Additionally, Alv has entered a phase 1b/2 study in patients with higher-risk MDS (NCT03593915). In order to possibly identify biomarkers of response, we performed a comprehensive pre-clinical in vitro assessment of Alv combined with 5-Aza using a clinically well-characterized cohort of n=40 MDS (high risk) patients and n=11 healthy controls. CD34+ HSCs were purified from bone marrow (BM) aspirates using positive selection with MACS microbeads. CD34+ cells of healthy controls were obtained from femur head replacement surgery bone specimens. Hematopoietic stem cells (HSCs) were expanded for four days in StemSpan SFEM II medium containing StemSpan Myeloid Expansion Supplement (Stem Cell Technologies) and treated with 5-Aza for 48h, Alv for 24h or their sequential combination (5-Aza for 48h followed by Alv for 24h). Cell viability was determined using CellTiter-Glo and Annexin-V apoptosis assays. MDS recurrent mutations in BM mononuclear cells were assessed using myeloid NGS panel deep sequencing containing 67 genes. The combination of 5-Aza+Alv showed an additive cytotoxic effect on CD34+ MDS cells in CellTiter- Glo cell viability assays (median cell viability = 74%, 73.8% and 55% for 5-Aza, Alv and combination respectively, p<0.0001). In annexin-V apoptotic assay, MDS cells were more sensitive to the cytotoxic effect of the combination treatment compared to healthy CD34+ cells (median % of apoptotic and dead cells = 36.6% for MDS vs 25.6% for healthy group, p=0.0288). Of note, the presence of ASXL1 and ZRSR2 mutations was associated with higher cytotoxic activity of 5-Aza+Alv combination. In particular, ZRSR2 mutations had an independent impact on the cell viability in a multivariable analysis (p=0.035). Overall, we provided pre-clinical support for the use of 5-Aza+Alv combination for higher risks MDS and identified ASXL1 and ZRSR2 mutations as potential genetic biomarkers of response. Disclosures Schmitt: Affimed GmbH: Research Funding. Jawhar: Celgene: Other: Travel support; Takeda: Honoraria, Other: Travel support; Stemline: Consultancy, Honoraria; Blueprint Medicines: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Foulks: Sumitomo Dainippon Pharma Oncology: Patents & Royalties: WO2021102343A1; Sumitomo Dainippon Pharma Oncology: Patents & Royalties: CA3103995A1; Sumitomo Dainippon Pharma Oncology: Patents & Royalties: US11040038B2. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Nowak: Celgene: Honoraria; Takeda: Honoraria; Affimed: Research Funding; Pharmaxis: Current holder of individual stocks in a privately-held company, Research Funding; AbbVie: Other: Investigator on funded clinical trial; Tolero Pharma, Pharmaxis, Apogenix: Research Funding.
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Ryabov, Vladimir, Nanni Schmitt, Qingyu Xu, Alexander Streuer, Johann-Christoph Jann, Alina Wein, Eva Altrock, et al. "Abstract 6257: Mutations in the ASXL1 and ZRSR2 genes are associated with the response to the combination of alvocidib and 5-azacytidine in higher-risk myelodysplastic syndromes." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6257. http://dx.doi.org/10.1158/1538-7445.am2022-6257.
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Abstract The hypomethylating agent 5-azacytidine (5-Aza) is a standard-of-care for patients with higher-risk myelodysplastic syndromes (MDS). Although an initial response is induced in approximately 50% of 5-Aza treated patients, subsequent relapse is almost certain. Recently, inhibitors of anti-apoptotic BCL-2 protein family members have shown therapeutic potential in acute myeloid leukemia (AML) and higher-risk MDS. Alvocidib (Alv), a CDK9 inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has shown anti-leukemic effects in a phase 1 study of patients with AML (Lee DJ et al, Expert Opin Investig Drugs 2019; Zeidner JF et al, Leuk Res 2015). A phase 1b/2 study with Alv and 5-Aza or decitabine in higher-risk patients with MDS was recently completed (NCT03593915); however, biomarkers for response to the Alv and 5-Aza combination are not well characterized. To identify potential biomarkers of response, we performed a comprehensive in vitro assessment of Alv and 5-Aza combination using a clinically well-characterized cohort of n=45 higher-risk patients with MDS and n=11 healthy controls (HC). CD34+ cells were purified from bone marrow (BM) aspirates using positive selection with MACS beads. CD34+ cells of HC were obtained from femur head replacement surgery bone specimens. After 4 days of expansion in SFEM II medium containing StemSpan Myeloid Expansion Supplement, cells were treated with 5-Aza for 48h, Alv for 24h or their combination (5-Aza for 48h followed by Alv for 24h). Cell viability was determined using CellTiter-Glo (CTG) and Annexin-V apoptosis assays. MCL-1 dependency of MDS samples was assessed using MS1 peptide-based assay. Recurrent myeloid neoplasia mutations in 67 genes were assessed in BM mononuclear cells using NGS panel deep sequencing. The combination of 5-Aza+Alv had an additive cytotoxic effect on CD34+ MDS cells in CTG assay (median cell viability = 74%, 73.8% and 55% for 5-Aza, Alv and combination respectively, p<0.0001). In Annexin-V apoptosis assay, MDS samples were more sensitive to the combination treatment compared to HC (median % of apoptotic and dead cells = 36.6% for MDS vs 25.6% for HC, p=0.0288). MCL-1 dependency inversely and not significantly correlated with CD34+ cell viability in CTG assays (Spearman r=-0.37, p=0.1119). In contrast, we found significant associations between ASXL1 and ZRSR2 mutations and higher sensitivity of MDS samples to 5-Aza+Alv combination (p=0.008 and p=0.0005 in univariable analysis respectively). ZRSR2 mutations also retained an independent impact on cell viability in multivariable analysis (p=0.035). Overall, we provide pre-clinical support for the use of 5-Aza+Alv combination for higher-risk MDS and identified ASXL1 and ZRSR2 mutations as potential genetic biomarkers of augmented response. Citation Format: Vladimir Ryabov, Nanni Schmitt, Qingyu Xu, Alexander Streuer, Johann-Christoph Jann, Alina Wein, Eva Altrock, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Ahmed Jawhar, Ali Darwich, Patrick Wuchter, Christel Weiss, Georgia Metzgeroth, Jason M. Foulks, Laurenz Steiner, Mohamad Jawhar, Wolf-Karsten Hofmann, Daniel Nowak. Mutations in the ASXL1 and ZRSR2 genes are associated with the response to the combination of alvocidib and 5-azacytidine in higher-risk myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6257.
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Shen, L., Y. Zhang, Z. Honglin, and J. H. W. Distler. "POS0476 THE NUCLEAR RECEPTOR TR4 ORCHESTRATES CYTOSKELETAL ORGANIZATION IN A Gα12/ROCK-DEPENDENT MANNER TO PROMOTE MYOFIBROBLAST DIFFERENTIATION AND TISSUE FIBROSIS IN SYSTEMIC SCLEROSIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 492.2–493. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2033.
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BackgroundNuclear receptors (NR) are a family of transcription factors. Several members of the NR family are candidates for targeted intervention in inflammatory and fibrotic diseases (1-2). Testicular receptor 4 (TR4), also known as Nr2c2, has been shown to regulate fundamental cellular processes such as differentiation, proliferation and growth factor signaling (3-4). However, its role in fibrotic diseases has not been investigated so far.ObjectivesThe aim of the present study was to characterize the role of TR4 in the pathogenesis of fibrotic tissue remodeling in SSc and to interrogate its underlying mechanism.MethodsExpression of TR4 was quantified by RT-PCR, Western blot and immunofluorescence. The effects of TR4 knockdown on collagen production and myofibroblast differentiation were analyzed in cultured human fibroblasts and in three mouse models with fibroblast-specific knockout of TR4. RNA sequencing was performed in TGFβ-stimulated human dermal fibroblasts transfected with TR4 siRNA or non-targeting siRNA. The implication of TR4 in cytoskeleton regulation was analyzed by ROCK activity assays, stress fiber formation and quantification of the ratio of filamentous (F)-actin/ globular (G)-actin. The functional role of ROCK and Gα12 was analyzed using small molecule inhibitors and siRNA, respectively.ResultsTR4 expression was upregulated in fibroblasts in the skin of SSc patients and fibrotic mouse models. The expression of TR4 was upregulated in a TGFβ- and SMAD3-dependent manner. TR4 knockdown inhibited TGFβ-induced myofibroblast differentiation and collagen release, whereas overexpression of TR4 promoted fibroblast activation. Fibroblastspecific knockout of TR4 ameliorated experimental dermal fibrosis induced by bleomycin, adTBR and in sclGVHD with decreases in dermal thickening, myofibroblast counts and hydroxyproline content. The RNASeq of TR4 knockdown fibroblasts stimulated with TGFβ identified 651 differentially expressed genes as compared to control fibroblasts. Differentially expressed genes included central profibrotic genes such as ACTA2, COL3A1, CCL12. gProfiler enrichment analysis of the TR4-DEGs revealed enrichment of multiple GO, GSEA and Reactome terms related to ECM release, cytoskeleton organization and Rho GTPases activity. Indeed, knockdown of TR4 ameliorated the induction of ROCK activity by TGFβ stimulation and reduced the shift in the ratio from globular (G) actin to filamentous (F) actin. Knockdown of TR4 strongly reduced the expression of the G-protein alpha-12 (Gα12). ROCK inhibition by Y27632 or knockdown of Gα12 inhibited the induction of αSMA and stress fiber formation induced by overexpression of TR4.ConclusionTR4 is upregulated in SSc in a TGFβ-dependent manner to promote fibroblast activation. Inhibition of TR4 interferes with TGFβ-induced activation of ROCK, prevents cytoskeletal remodeling and fibroblast-to-myofibroblast transition and ameliorates experimental fibrosis. As nuclear receptors are common targets for therapeutic intervention, TR4 may offer potential for antifibrotic therapies.References[1]Avouac J, Palumbo-Zerr K, et al. The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor beta and contributes to the development of experimental dermal fibrosis. Arthritis Rheumatol. 2014;66(11):3140-50.[2]Palumbo-Zerr K, Zerr P, et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis. Nat Med. 2015;21(2):150-8.[3]Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell. 2006;126(4):789-99.[4]Simandi Z, Cuaranta-Monroy I, Nagy L. Nuclear receptors as regulators of stem cell and cancer stem cell metabolism. Seminars in cell & developmental biology. 2013;24(10-12):716-23.Disclosure of InterestsLichong Shen: None declared, Yun Zhang: None declared, ZHU Honglin: None declared, Jörg H.W. Distler Shareholder of: stock owner of 4D Science GmbH, Consultant of: JHWD has consultancy relationships and/or has received research funding from AbbVie, Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma and Active Biotech in the area of potential treatments of SSc.
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Im, Eunju, Lang Yoo, Minju Hyun, Woo Hyun Shin, and Kwang Chul Chung. "Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin." Open Biology 6, no. 8 (August 2016): 160193. http://dx.doi.org/10.1098/rsob.160193.
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Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1 , PARK7 (DJ-1), LRRK2 and ATP13A2 . Many pathogenic mutations of PARK2 , which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis.
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Gupta, Manish K., Puneet Kaur Randhawa, and Michal M. Masternak. "Role of BAG5 in Protein Quality Control: Double-Edged Sword?" Frontiers in Aging 3 (March 3, 2022). http://dx.doi.org/10.3389/fragi.2022.844168.
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Cardiovascular disorder is the major health burden and cause of death among individuals worldwide. As the cardiomyocytes lack the ability for self-renewal, it is utmost necessary to surveil the protein quality in the cells. The Bcl-2 associated anthanogene protein (BAG) family and molecular chaperones (HSP70, HSP90) actively participate in maintaining cellular protein quality control (PQC) to limit cellular dysfunction in the cells. The BAG family contains a unique BAG domain which facilitates their interaction with the ATPase domain of the heat shock protein 70 (HSP70) to assist in protein folding. Among the BAG family members (BAG1-6), BAG5 protein is unique since it has five domains in tandem, and the binding of BD5 induces certain conformational changes in the nucleotide-binding domain (NBD) of HSP70 such that it loses its affinity for binding to ADP and results in enhanced protein refolding activity of HSP70. In this review, we shall describe the role of BAG5 in modulating mitophagy, endoplasmic stress, and cellular viability. Also, we have highlighted the interaction of BAG5 with other proteins, including PINK, DJ-1, CHIP, and their role in cellular PQC. Apart from this, we have described the role of BAG5 in cellular metabolism and aging.
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Weng, Huidan, Wenjing Song, Kangyue Fu, Yunqian Guan, Guoen Cai, En Huang, Xiaochun Chen, Haiqiang Zou, and Qinyong Ye. "Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model." Frontiers in Neuroscience 16 (January 25, 2023). http://dx.doi.org/10.3389/fnins.2022.1035444.
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IntroductionParkinson’s disease (PD), as a common neurodegenerative disease, currently has no effective therapeutic approaches to delay or stop its progression. There is an urgent need to further define its pathogenesis and develop new therapeutic targets. An increasing number of studies have shown that members of the sirtuin (SIRT) family are differentially involved in neurodegenerative diseases, indicating their potential to serve as targets in therapeutic strategies. Mitochondrial SIRT4 possesses multiple enzymatic activities, such as deacetylase, ADP ribosyltransferase, lipoamidase, and deacylase activities, and exhibits different enzymatic activities and target substrates in different tissues and cells; thus, mitochondrial SIRT4 plays an integral role in regulating metabolism. However, the role and mechanism of SIRT4 in PD are not fully understood. This study aimed to investigate the potential mechanism and possible regulatory targets of SIRT4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice.MethodsThe expression of the SIRT4 protein in the MPTP-induced PD mouse mice or key familial Parkinson disease protein 7 knockout (DJ-1 KO) rat was compared against the control group by western blot assay. Afterwards, quantitative proteomics and bioinformatics analyses were performed to identify altered proteins in the vitro model and reveal the possible functional role of SIRT4. The most promising molecular target of SIRT4 were screened and validated by viral transfection, western blot assay and reverse transcription quantitative PCR (RT-qPCR) assays.ResultsThe expression of the SIRT4 protein was found to be altered both in the MPTP-induced PD mouse mice and DJ-1KO rats. Following the viral transfection of SIRT4, a quantitative proteomics analysis identified 5,094 altered proteins in the vitro model, including 213 significantly upregulated proteins and 222 significantly downregulated proteins. The results from bioinformatics analyses indicated that SIRT4 mainly affected the ribosomal pathway, propionate metabolism pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and peroxisome pathway in cells, and we screened 25 potential molecular targets. Finally, only fatty acid binding protein 4 (FABP4) in the PPAR signaling pathway was regulated by SIRT4 among the 25 molecules. Importantly, the alterations in FABP4 and PPARγ were verified in the MPTP-induced PD mouse model.DiscussionOur results indicated that FABP4 in the PPAR signaling pathway is the most promising molecular target of SIRT4 in an MPTP-induced mouse model and revealed the possible functional role of SIRT4. This study provides a reference for future drug development and mechanism research with SIRT4 as a target or biomarker.