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November 7, 2022Amsterdam, the Netherlands – argenx (Euronext & Nasdaq: ARGX), a global immunology company committed to improving the lives of people suffering from severe autoimmune diseases, today announced that members of management will participate in several upcoming investor conferences in November:
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Taking years off your age? This Israeli expert says its all up to you Haaretz
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Taking years off your age? This Israeli expert says its all up to you - Haaretz
. 2020 Mar;16(3):512-530. doi: 10.1080/15548627.2019.1630222. Epub 2019 Jun 24. Seonghee Jung 1 ,Seongwon Choe 1 ,Hanwoong Woo 1 ,Hyeonjeong Jeong 1 ,Hyun-Kyu An 1 ,Hyewon Moon 1 ,Hye Young Ryu 1 ,Bo Kyoung Yeo 1 ,Ye Won Lee 1 ,Hyosun Choi 2 ,Ji Young Mun 3 ,Woong Sun 4 ,Han Kyoung Choe 1 ,Eun-Kyoung Kim 1 5 ,Seong-Woon Yu 1 5
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Seonghee Junget al. Autophagy. 2020 Mar.
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Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders.Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2'-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3'-diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.
Keywords: Atg7 knockout; autophagic cell death; corticosterone; hippocampal neurogenesis; serum/glucocorticoid regulated kinase 3; stress.
Figure 1.
Chronic restraint stress (CRS)-induced reduction
Figure 1.
Chronic restraint stress (CRS)-induced reduction in the number of adult hippocampal NSCs is
Chronic restraint stress (CRS)-induced reduction in the number of adult hippocampal NSCs is prevented by Atg7 deletion. (A) Scheme of mouse breeding and experimental time line for generation of tamoxifen (TAM)-inducible NSC-specific Atg7-NSC cKO mice. (B) Gene dosedependence of ATG7 immunofluorescence intensities in the DG of the hippocampus. Scale bar: 50 m. Solid and dotted circles indcate granule neurons and NSCs, respectively. The graph shows quantification of SOX2+ and ATG7+ cells (n =6). (c) Timeline of the experiment. (D) Representative images of BrdU and SOX2 staining in the subgranular zone (SGZ) of the hippocampus. Scale bar: 20 m. The graph on the right shows quantification of BrdU+ and SOX2+ cells (n =68 per group). (E) Immunofluorescence of SOX2, NES and VIM in the SGZ of the DG of the hippocampus. Scale bar: 50 m. Arrows indicate NSCs positive for each marker. ***P <0.001 for the total SOX2+ cells. ###P <0.001 for BrdU+ SOX2+ cells. n.s., not significant.
Figure 2.
CRS induces autophagy in adult
Figure 2.
CRS induces autophagy in adult hippocampal NSCs. ( A ) Work flow of
CRS induces autophagy in adult hippocampal NSCs. (A) Work flow of correlative light electron microscopy (CLEM) imaging. (B) CLEM imaging of SOX2-positive cells at day-4 of CRS (n =13 cells per group). Representative images of autophagosomes (white arrows) in CRS group are shown at higher magnification. The number of autophagosomes was counted per 5m5m without counting the autophagosomes of whole cells using serial sections. Scale bars: 2 m. (C) Nes promoter-driven lentiviral expression of mRFP-EGFP-MAP1LC3B in vivo. Virus was injected 4days prior to CRS and analyzed at day 2 of CRS. Scale bar: 20 m. The graph on the right shows quantification of autophagosomes and autolysosomes (n =7 or 8 cells per group). (D and E) Cleaved CASP3 (c.CASP3) staining (D) and TUNEL assay (E) in the DG at day 7 of CRS. STS was injected 12h before analysis. Arrows indicate c.CASP3-positive cells. Scale bar: 100 m. ***P <0.001. n.s., not significant.
Figure 3.
Suppression of hippocampal neurogenesis, anxiety-like
Figure 3.
Suppression of hippocampal neurogenesis, anxiety-like and depressive behaviors, and spatial memory deficits induced
Suppression of hippocampal neurogenesis, anxiety-like and depressive behaviors, and spatial memory deficits induced by CRS are prevented in Atg7-NSC cKO mice. (A) Timeline for the measurement of the number of BrdU+ and RBFOX3+ double-positive NSCs. (B) Representative images of BrdU+ RBFOX3+ staining. Scale bar: 20 m. Arrow indicate RBFOX3+ BrdU+ double-positive cells. (C) Quantification of BrdU+ RBFOX3+-positive cells (n =6 or 7 per group). (D and E) Measurement of anxiety-like behaviors by the open field test (n =6 or 7 per group) (D) and elevated plus maze test (n =613 per group) (E). (F) Measurement of depressive behavior by the sucrose preference test (n =6). (G) Assessment of spatial working memory by the Y-maze test (n =68 per group). (H) Spatial learning and memory test using the acquisition phase (left graph) and probe test at day 6 (right graph) in MWM test (n =68 per group). TQ, target quadrant; AL, adjacent left; AR, adjacent right; OP, opposite. *P <0.05, **P <0.01, ***P <0.001.
Figure 4.
Atg7 deficiency prevents loss of
Figure 4.
Atg7 deficiency prevents loss of subtypes of NSCs in the adult DG and
Atg7 deficiency prevents loss of subtypes of NSCs in the adult DG and the activity of NSCs in neurosphere cultures. (A) Representative image of each subtype of NSCs in the SGZ of the DG. (band c) Quantification of GFAP+ SOX2+ (type 1), GFAP+ SOX2+ MKI67+ (active type 1), ASCL1+ SOX2+ (type 2a), DCX+ SOX2+ (type 2b), and DCX+ (type 3) NSCs 1 day (n =4 or 5 per group) (B) and 28days after CRS (n =5 or 6 per group) (C). (D) Representative image of neurospheres in culture for 7days. Scale bar: 40 m. (E) Quantification of neurospheres after 7days in cultures (n =35 per group). (F) Measurement of neurosphere size after 7days in cultures (n =35 per group). *P <0.05, **P <0.01, ***P <0.001.
Figure 5.
CORT-induced reduction of NSC number
Figure 5.
CORT-induced reduction of NSC number and hippocampal dysfuction is prevented in Atg7-NSC cKO
CORT-induced reduction of NSC number and hippocampal dysfuction is prevented in Atg7-NSC cKO mice. (A) Timeline of the CORT injection experiment. (B) Quantification of BrdU+ and SOX2+ cells (n =4 or 5 per group). **P <0.01 for the total SOX2+ cells ##P <0.01 for BrdU+ SOX2+ cells. (C) Nes promoter-driven lentiviral expression of mRFP-EGFP-MAPLC3B in SOX2+ cells in vivo. Scale bar: 20m. The graph on the right shows quantification of autophagosomes and autolysosomes (n =7 or 8 cells per group). (D) Timeline for the measurement of the number of BrdU+ RBFOX3+ doublepositive NSCs. (E) Quantification of BrdU+ RBFOX3+ double-positive cells (n =4 or 5 per group). (f) Elevated plus maze test (n =4 per group). (g) Y-maze test (n =4 per group). *P <0.05, **P <0.01, ***P <0.001.
Figure 6.
CORT treatment does not induce
Figure 6.
CORT treatment does not induce apoptosis or necroptosis in HCN cells. ( A
CORT treatment does not induce apoptosis or necroptosis in HCN cells. (A) Death rate of HCN cells after CORT treatment (n =4). Right, representative image of Hoechst and PI staining 48h after CORT treatment in HCN cells. (B) Nucleus condensation assay with Hoechst staining. (C) Immunostaining of cleaved CASP3 (c.CASP3). (D) Nuclear fragmentation assay by TUNEL staining. Scale bar: 40m for b-d. (E and F) Agarose gel electrophoresis of DNA fragmentation assay (E) and western blots of c.CASP3 (F) are representative of at least 3 experiments with similar results. All apoptotic markers were analyzed after CORT (200M for 48h, except western blotting analysis of c.CASP3 with 72h) or staurosporine (STS, 0.5M for 6h) treatment. (G) Effects of Z-VAD (25 M) or necrostatin-1 (NEC-1, 100 M) on HCN cell death after CORT treatment for 48h (n =3). (H) Western blotting analysis of the effects of Z-VAD (25 M) on autophagy flux after CORT treatment for 48h. The blots are representative of 3 experiments with similar results. *P <0.05, **P <0.01, ***P <0.001. n.s., not significant.
Figure 7.
CORT treatment induces ACD in
Figure 7.
CORT treatment induces ACD in HCN cells. ( A ) Representative EM images
CORT treatment induces ACD in HCN cells. (A) Representative EM images of HCN cells treated with CORT for 48h. Scale bar: 2 m. N, nucleus. The graph on the right shows quantification of autophagosomes (n =35 cells per group). (B) Western blotting analyses of MAP1LC3B and SQSTM1 levels after CORT treatment for 48h. The graphs on the right show quantification of MAP1LC3B-II (n =6) and SQSTM1 (n =4) after normalization to ACTB. (C) Analysis of autophagy flux using mRFP-EGFP-MAP1LC3B after CORT treatment for 48h. Scale bar: 10m. The graph on the right shows quantification of MAP1LC3B puncta (n =8). ***P <0.001 for the total MAP1LC3B puncta. #P <0.05, ##P <0.01 for yellow puncta. (D) Death rates of HCN cells after KO of Ulk1 (sgUlk1) or with stable knockdown of ATG7 (shAtg7), SQSTM1 (shSqstm1) or MAP1LC3B (shMap1lc3b) in comparison with control cells (sgCon or shCon) after CORT treatment for 48h (n =3). In all experiments, BafA1 (20nM) was added 1 h before cell harvest. *P <0.05, **P <0.01, ***P <0.001.
Figure 8.
SGK3 is critical for CORT-induced
Figure 8.
SGK3 is critical for CORT-induced cell death, but dispensable for apoptosis or necroptosis
SGK3 is critical for CORT-induced cell death, but dispensable for apoptosis or necroptosis in HCN cells. (A and B) Changes in the expression levels of SGK1, 2, and 3 following CORT treatment in HCN cells. mRNA levels after CORT treatment for 24h (n =3) (A). Western blotting analyses of protein levels (B). Blots are representative of 3 experiments with similar results. (C) KO of Sgk1 (sgSgk1) and Sgk2 (sgSgk2). (D) Death rates of sgSgk1 and sgSgk2 cells after CORT treatment for 48h (n =3). (E) KO of Sgk3 (sgSgk3). (F) Death rate of sgSgk3 cells (n =8). (G) Death rate of sgSgk3 cells after STS treatment (0.5 M) for 24h (n =3). (G) Death rate of sgSgk3 cells after H2O2 treatment (100M) for 6h (n =3). ***P <0.001. n.s., not significant.
Figure 9.
SGK3 mediates ACD in HCN
Figure 9.
SGK3 mediates ACD in HCN cells following CORT treatment. ( A ) Analysis
SGK3 mediates ACD in HCN cells following CORT treatment. (A) Analysis of autophagy flux by western blotting of MAP1LC3B. The graph shows quantification of MAP1LC3B-II after normalization to ACTB (n =5). (B) Analysis of autophagosome formation using mRFP-MAP1LC3B. Scale bar: 10m. The graph shows quantification of autophagosomes (n =4 or 5). (C) Time-course analysis of EGFP-ZFYVE1 puncta formation after CORT treatment using EGFP-ZFYVE1. Scale bar: 10m. The graph shows quantification of ZFYVE1 puncta (n =46). (D) Domain diagrams of SGK1, 2, and 3 showing the critical Arg90 residue in the Phox homology (PX) domain in SGK3. SGK1 has an incomplete PX domain [38]. (E) Effects of SGK3WT and SGK3R90A mutant on sgSgk3 cell death (n =4). EV, empty vector. (F) Analysis of autophagy flux by western blotting of MAP1LC3B in sgSgk3 cells transfected with SGK3WT or SGK3R90A mutant. The graph shows quantification of MAP1LC3B-II after normalization to ACTB (n =3). (G) Effects of the SGK3R90A mutation on the MAP1LC3B puncta formation and colocalization of SGK3 with MAP1LC3B. sgSgk3 cells were co-transfected with EGFP-tagged SGK3WT or SGK3R90A mutant with mRFP-MAP1LC3B. Scale bar: 10 m. In all experiments, BafA1 (20nM) was added 1 h before cell harvest. *P <0.05, ***P <0.001. n.s., not significant.
Figure 10.
SGK3 silencing attenuates NSC reduction
Figure 10.
SGK3 silencing attenuates NSC reduction in the DG after CRS. ( A )
SGK3 silencing attenuates NSC reduction in the DG after CRS. (A) Experimental design illustrating stereotaxic injection of AAV1/2-guide RNAs into DG of S-Cas9 KI mice. (B) Image of AAV1/2-sgSGK3-mCherry expression in the SGZ of DG. Scale bar, 100m. (C) KO of Sgk1 (AAV-sgSgk1) and Sgk3 (AAV-sgSgk3). (D) Timeline of the experiment. (E) Representative images of mCherry and SOX2 co-labeling in the SGZ of DG 3weeks after injection of AAV-sgSgk1 or AAV-sgSgk3 in S-Cas9 mice. Scale bar, 50m. (F) The graph shows quantification of SGK-mCherry and SOX2 double-positive cells. (n =5). ***P <0.001.
All figures (10)
An HK, Chung KM, Park H, Hong J, Gim JE, Choi H, Lee YW, Choi J, Mun JY, Yu SW. An HK, et al. Autophagy. 2020 Sep;16(9):1598-1617. doi: 10.1080/15548627.2019.1695398. Epub 2019 Dec 10. Autophagy. 2020. PMID: 31818185 Free PMC article.
Wang C, Haas M, Yeo SK, Sebti S, Fernndez F, Zou Z, Levine B, Guan JL. Wang C, et al. Autophagy. 2022 Feb;18(2):409-422. doi: 10.1080/15548627.2021.1936358. Epub 2021 Jun 8. Autophagy. 2022. PMID: 34101533 Free PMC article.
Devis-Jauregui L, Eritja N, Davis ML, Matias-Guiu X, Llobet-Navs D. Devis-Jauregui L, et al. Autophagy. 2021 May;17(5):1077-1095. doi: 10.1080/15548627.2020.1752548. Epub 2020 May 13. Autophagy. 2021. PMID: 32401642 Free PMC article. Review.
Wan H, Wang Q, Chen X, Zeng Q, Shao Y, Fang H, Liao X, Li HS, Liu MG, Xu TL, Diao M, Li D, Meng B, Tang B, Zhang Z, Liao L. Wan H, et al. Autophagy. 2020 Mar;16(3):531-547. doi: 10.1080/15548627.2019.1630224. Epub 2019 Jun 23. Autophagy. 2020. PMID: 31204559 Free PMC article.
You Z, Xu Y, Wan W, Zhou L, Li J, Zhou T, Shi Y, Liu W. You Z, et al. Autophagy. 2019 Aug;15(8):1309-1321. doi: 10.1080/15548627.2019.1580510. Epub 2019 Feb 20. Autophagy. 2019. PMID: 30767704 Free PMC article.
Atrooz F, Alkadhi KA, Salim S. Atrooz F, et al. Curr Res Neurobiol. 2021 May 23;2:100013. doi: 10.1016/j.crneur.2021.100013. eCollection 2021. Curr Res Neurobiol. 2021. PMID: 36246514 Free PMC article. Review.
Sun L, Zou Y, Su P, Xue C, Wang D, Zhao F, Luo W, Zhang J. Sun L, et al. Oxid Med Cell Longev. 2022 Oct 4;2022:7676872. doi: 10.1155/2022/7676872. eCollection 2022. Oxid Med Cell Longev. 2022. PMID: 36238644 Free PMC article.
Llorente V, Velarde P, Desco M, Gmez-Gaviro MV. Llorente V, et al. Cells. 2022 Sep 26;11(19):3002. doi: 10.3390/cells11193002. Cells. 2022. PMID: 36230964 Free PMC article. Review.
Wang C, Shen Y, Ni J, Hu W, Yang Y. Wang C, et al. Cell Mol Life Sci. 2022 Aug 16;79(9):485. doi: 10.1007/s00018-022-04455-3. Cell Mol Life Sci. 2022. PMID: 35974132 Review.
Tang CF, Wang CY, Wang JH, Wang QN, Li SJ, Wang HO, Zhou F, Li JM. Tang CF, et al. Nutrients. 2022 Apr 29;14(9):1882. doi: 10.3390/nu14091882. Nutrients. 2022. PMID: 35565849 Free PMC article.
Show all 38 references
This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04].
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Autophagic death of neural stem cells mediates chronic stress-induced ...
Death of a cell mediated by intracellular program, often as part of development
Programmed cell death (PCD; sometimes referred to as cellular suicide[1]) is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy.[2][3] PCD is carried out in a biological process, which usually confers advantage during an organism's lifecycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development.
Apoptosis and autophagy are both forms of programmed cell death.[4] Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Necrosis was long seen as a non-physiological process that occurs as a result of infection or injury,[4] but in the 2000s, a form of programmed necrosis, called necroptosis,[5] was recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Most recently, other types of regulated necrosis have been discovered as well, which share several signaling events with necroptosis and apoptosis.[6]
The concept of "programmed cell-death" was used by Lockshin & Williams[7] in 1964 in relation to insect tissue development, around eight years before "apoptosis" was coined. The term PCD has, however, been a source of confusion and Durand and Ramsey[8] have developed the concept by providing mechanistic and evolutionary definitions. PCD has become the general terms that refers to all the different types of cell death that have a genetic component.
The first insight into the mechanism came from studying BCL2, the product of a putative oncogene activated by chromosome translocations often found in follicular lymphoma. Unlike other cancer genes, which promote cancer by stimulating cell proliferation, BCL2 promoted cancer by stopping lymphoma cells from being able to kill themselves.[9]
PCD has been the subject of increasing attention and research efforts. This trend has been highlighted with the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (United Kingdom), H. Robert Horvitz (US) and John E. Sulston (UK).[10]
Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms.[12] Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. It is now thought that- in a developmental context- cells are induced to positively commit suicide whilst in a homeostatic context; the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.[13]
Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles.
Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection and cancer.
A critical regulator of autophagy induction is the kinase mTOR, which when activated, suppresses autophagy and when not activated promotes it. Three related serine/threonine kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, Beclin-1, p150 and Atg14-like protein or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy.
The ATG genes control the autophagosome formation through ATG12-ATG5 and LC3-II (ATG8-II) complexes. ATG12 is conjugated to ATG5 in a ubiquitin-like reaction that requires ATG7 and ATG10. The Atg12Atg5 conjugate then interacts non-covalently with ATG16 to form a large complex. LC3/ATG8 is cleaved at its C terminus by ATG4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane.
Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism, however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.
Besides the above two types of PCD, other pathways have been discovered.[14]Called "non-apoptotic programmed cell-death" (or "caspase-independent programmed cell-death" or "necroptosis"), these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD.
Other forms of programmed cell death include anoikis, almost identical to apoptosis except in its induction; cornification, a form of cell death exclusive to the eyes; excitotoxicity; ferroptosis, an iron-dependent form of cell death[15] and Wallerian degeneration.
Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. Nemosis is another programmed form of necrosis that takes place in fibroblasts.[16]
Eryptosis is a form of suicidal erythrocyte death.[17]
Aponecrosis is a hybrid of apoptosis and necrosis and refers to an incomplete apoptotic process that is completed by necrosis.[18]
NETosis is the process of cell-death generated by NETs.[19]
Paraptosis is another type of nonapoptotic cell death that is mediated by MAPK through the activation of IGF-1. It's characterized by the intracellular formation of vacuoles and swelling of mitochondria.[20]
Pyroptosis, an inflammatory type of cell death, is uniquely mediated by caspase 1, an enzyme not involved in apoptosis, in response to infection by certain microorganisms.[20]
Plant cells undergo particular processes of PCD similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa.
An atrophic factor is a force that causes a cell to die. Only natural forces on the cell are considered to be atrophic factors, whereas, for example, agents of mechanical or chemical abuse or lysis of the cell are considered not to be atrophic factors.[by whom?] Common types of atrophic factors are:[21]
The initial expansion of the developing nervous system is counterbalanced by the removal of neurons and their processes.[22] During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD).[23] PCD in the nervous system was first recognized in 1896 by John Beard.[24] Since then several theories were proposed to understand its biological significance during neural development.[25]
PCD in the developing nervous system has been observed in proliferating as well as post-mitotic cells.[22] One theory suggests that PCD is an adaptive mechanism to regulate the number of progenitor cells. In humans, PCD in progenitor cells starts at gestational week 7 and remains until the first trimester.[26] This process of cell death has been identified in the germinal areas of the cerebral cortex, cerebellum, thalamus, brainstem, and spinal cord among other regions.[25] At gestational weeks 1923, PCD is observed in post-mitotic cells.[27] The prevailing theory explaining this observation is the neurotrophic theory which states that PCD is required to optimize the connection between neurons and their afferent inputs and efferent targets.[25] Another theory proposes that developmental PCD in the nervous system occurs in order to correct for errors in neurons that have migrated ectopically, innervated incorrect targets, or have axons that have gone awry during path finding.[28] It is possible that PCD during the development of the nervous system serves different functions determined by the developmental stage, cell type, and even species.[25]
The neurotrophic theory is the leading hypothesis used to explain the role of programmed cell death in the developing nervous system.[29] It postulates that in order to ensure optimal innervation of targets, a surplus of neurons is first produced which then compete for limited quantities of protective neurotrophic factors and only a fraction survive while others die by programmed cell death.[26] Furthermore, the theory states that predetermined factors regulate the amount of neurons that survive and the size of the innervating neuronal population directly correlates to the influence of their target field.[30]
The underlying idea that target cells secrete attractive or inducing factors and that their growth cones have a chemotactic sensitivity was first put forth by Santiago Ramon y Cajal in 1892.[31] Cajal presented the idea as an explanation for the "intelligent force" axons appear to take when finding their target but admitted that he had no empirical data.[31] The theory gained more attraction when experimental manipulation of axon targets yielded death of all innervating neurons. This developed the concept of target derived regulation which became the main tenet in the neurotrophic theory.[32][33] Experiments that further supported this theory led to the identification of the first neurotrophic factor, nerve growth factor (NGF).[34]
Different mechanisms regulate PCD in the peripheral nervous system (PNS) versus the central nervous system (CNS). In the PNS, innervation of the target is proportional to the amount of the target-released neurotrophic factors NGF and NT3.[35][36] Expression of neurotrophin receptors, TrkA and TrkC, is sufficient to induce apoptosis in the absence of their ligands.[23] Therefore, it is speculated that PCD in the PNS is dependent on the release of neurotrophic factors and thus follows the concept of the neurotrophic theory.
Programmed cell death in the CNS is not dependent on external growth factors but instead relies on intrinsically derived cues. In the neocortex, a 4:1 ratio of excitatory to inhibitory interneurons is maintained by apoptotic machinery that appears to be independent of the environment.[36] Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured in vitro.[37] Transplanted cells died at the age of two weeks, the same age at which endogenous interneurons undergo apoptosis. Regardless of the size of the transplant, the fraction of cells undergoing apoptosis remained constant. Furthermore, disruption of TrkB, a receptor for brain derived neurotrophic factor (Bdnf), did not affect cell death. It has also been shown that in mice null for the proapoptotic factor Bax (Bcl-2-associated X protein) a larger percentage of interneurons survived compared to wild type mice.[37] Together these findings indicate that programmed cell death in the CNS partly exploits Bax-mediated signaling and is independent of BDNF and the environment. Apoptotic mechanisms in the CNS are still not well understood, yet it is thought that apoptosis of interneurons is a self-autonomous process.
Programmed cell death can be reduced or eliminated in the developing nervous system by the targeted deletion of pro-apoptotic genes or by the overexpression of anti-apoptotic genes. The absence or reduction of PCD can cause serious anatomical malformations but can also result in minimal consequences depending on the gene targeted, neuronal population, and stage of development.[25] Excess progenitor cell proliferation that leads to gross brain abnormalities is often lethal, as seen in caspase-3 or caspase-9 knockout mice which develop exencephaly in the forebrain.[38][39] The brainstem, spinal cord, and peripheral ganglia of these mice develop normally, however, suggesting that the involvement of caspases in PCD during development depends on the brain region and cell type.[40] Knockout or inhibition of apoptotic protease activating factor 1 (APAF1), also results in malformations and increased embryonic lethality.[41][42][43] Manipulation of apoptosis regulator proteins Bcl-2 and Bax (overexpression of Bcl-2 or deletion of Bax) produces an increase in the number of neurons in certain regions of the nervous system such as the retina, trigeminal nucleus, cerebellum, and spinal cord.[44][45][46][47][48][49][50] However, PCD of neurons due to Bax deletion or Bcl-2 overexpression does not result in prominent morphological or behavioral abnormalities in mice. For example, mice overexpressing Bcl-2 have generally normal motor skills and vision and only show impairment in complex behaviors such as learning and anxiety.[51][52][53] The normal behavioral phenotypes of these mice suggest that an adaptive mechanism may be involved to compensate for the excess neurons.[25]
Learning about PCD in various species is essential in understanding the evolutionary basis and reason for apoptosis in development of the nervous system. During the development of the invertebrate nervous system, PCD plays different roles in different species.[54] The similarity of the asymmetric cell death mechanism in the nematode and the leech indicates that PCD may have an evolutionary significance in the development of the nervous system.[55] In the nematode, PCD occurs in the first hour of development leading to the elimination of 12% of non-gonadal cells including neuronal lineages.[56] Cell death in arthropods occurs first in the nervous system when ectoderm cells differentiate and one daughter cell becomes a neuroblast and the other undergoes apoptosis.[57] Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females.[58] In Drosophila, PCD is essential in segmentation and specification during development.
In contrast to invertebrates, the mechanism of programmed cell death is found to be more conserved in vertebrates. Extensive studies performed on various vertebrates show that PCD of neurons and glia occurs in most parts of the nervous system during development. It has been observed before and during synaptogenesis in the central nervous system as well as the peripheral nervous system.[25] However, there are a few differences between vertebrate species. For example, mammals exhibit extensive arborization followed by PCD in the retina while birds do not.[59] Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.[25]
Programmed cell death in plants has a number of molecular similarities to animal apoptosis, but it also has differences, the most obvious being the presence of a cell wall and the lack of an immune system that removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuole that ruptures as the cell dies.[60]
In "APL regulates vascular tissue identity in Arabidopsis",[61] Martin Bonke and his colleagues had stated that one of the two long-distance transport systems in vascular plants, xylem, consists of several cell-types "the differentiation of which involves deposition of elaborate cell-wall thickenings and programmed cell-death." The authors emphasize that the products of plant PCD play an important structural role.
Basic morphological and biochemical features of PCD have been conserved in both plant and animal kingdoms.[62] Specific types of plant cells carry out unique cell-death programs. These have common features with animal apoptosisfor instance, nuclear DNA degradationbut they also have their own peculiarities, such as nuclear degradation triggered by the collapse of the vacuole in tracheary elements of the xylem.[63]
Janneke Balk and Christopher J. Leaver, of the Department of Plant Sciences, University of Oxford, carried out research on mutations in the mitochondrial genome of sun-flower cells. Results of this research suggest that mitochondria play the same key role in vascular plant PCD as in other eukaryotic cells.[64]
During pollination, plants enforce self-incompatibility (SI) as an important means to prevent self-fertilization. Research on the corn poppy (Papaver rhoeas) has revealed that proteins in the pistil on which the pollen lands, interact with pollen and trigger PCD in incompatible (i.e., self) pollen. The researchers, Steven G. Thomas and Vernonica E. Franklin-Tong, also found that the response involves rapid inhibition of pollen-tube growth, followed by PCD.[65]
The social slime mold Dictyostelium discoideum has the peculiarity of either adopting a predatory amoeba-like behavior in its unicellular form or coalescing into a mobile slug-like form when dispersing the spores that will give birth to the next generation.[66]
The stalk is composed of dead cells that have undergone a type of PCD that shares many features of an autophagic cell-death: massive vacuoles forming inside cells, a degree of chromatin condensation, but no DNA fragmentation.[67] The structural role of the residues left by the dead cells is reminiscent of the products of PCD in plant tissue.
D. discoideum is a slime mold, part of a branch that might have emerged from eukaryotic ancestors about a billion years before the present. It seems that they emerged after the ancestors of green plants and the ancestors of fungi and animals had differentiated. But, in addition to their place in the evolutionary tree, the fact that PCD has been observed in the humble, simple, six-chromosome D. discoideum has additional significance: It permits the study of a developmental PCD path that does not depend on caspases characteristic of apoptosis.[68]
The occurrence of programmed cell death in protists is possible,[69][70] but it remains controversial. Some categorize death in those organisms as unregulated apoptosis-like cell death.[71][72]
Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts ("living together inside") of larger eukaryotic cells. It was Lynn Margulis who from 1967 on championed this theory, which has since become widely accepted.[73] The most convincing evidence for this theory is the fact that mitochondria possess their own DNA and are equipped with genes and replication apparatus.
This evolutionary step would have been risky for the primitive eukaryotic cells, which began to engulf the energy-producing bacteria, as well as a perilous step for the ancestors of mitochondria, which began to invade their proto-eukaryotic hosts. This process is still evident today, between human white blood cells and bacteria. Most of the time, invading bacteria are destroyed by the white blood cells; however, it is not uncommon for the chemical warfare waged by prokaryotes to succeed, with the consequence known as infection by its resulting damage.
One of these rare evolutionary events, about two billion years before the present, made it possible for certain eukaryotes and energy-producing prokaryotes to coexist and mutually benefit from their symbiosis.[74]
Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide.[75] It is not clear why apoptotic machinery is maintained in the extant unicellular organisms. This process has now been evolved to happen only when programmed.[76] to cells (such as feedback from neighbors, stress or DNA damage), mitochondria release caspase activators that trigger the cell-death-inducing biochemical cascade. As such, the cell suicide mechanism is now crucial to all of our lives.
The BCR-ABL oncogene has been found to be involved in the development of cancer in humans.[77]
c-Myc is involved in the regulation of apoptosis via its role in downregulating the Bcl-2 gene. Its role the disordered growth of tissue.[77]
A molecular characteristic of metastatic cells is their altered expression of several apoptotic genes.[77]
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