Par-4: An Emerging Pivotal Player in Neuronal Apoptosis and Neurodegenerative Disorders

Mattson, Mark P.; Duan, Wenzhen; Chan, Sic L.; Camandola, Simonetta

doi:10.1385/jmn:13:1-2:17

Cited by 60 publications

(38 citation statements)

References 34 publications

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“…S3A, lane 4). Down-regulation of PAR-4 was concurrent with up-regulation of Bcl-2, an antiapoptotic protein whose expression is suppressed by PAR-4 (27,28), which confirmed that the knockdown was specific for PAR-4. Immunocytochemistry for PAR-4 showed that in shRNA-expressing cells (GFP-labeled), the level of amyloid-induced apoptosis (40 M A␤25-35) was less than 5% (supplemental Fig.…”

Section: Amyloid Peptide Induces Apoptosis In Astrocytes Inmentioning

confidence: 68%

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Wang¹,

Dinkins²,

He³

et al. 2012

Journal of Biological Chemistry

327

305

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Background:In AD, amyloid protein is associated with neurodegeneration, which may involve amyloid effects on astrocytes. Results: In astrocytes, amyloid peptide triggers secretion of proapoptotic exosomes ("apoxosomes") that are associated with ceramide and PAR-4. Conclusion: Activation of nSMase2 and expression of PAR-4 is critical for the secretion of apoxosomes and glial apoptosis. Significance: Apoxosomes may contribute to glial apoptosis, and therefore, neurodegeneration in AD.Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide-enriched exosomes, which may critically contribute to Alzheimer disease.

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Section: Amyloid Peptide Induces Apoptosis In Astrocytes Inmentioning

confidence: 68%

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Wang¹,

Dinkins²,

He³

et al. 2012

Journal of Biological Chemistry

327

305

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“…41,42 Western blot analysis revealed that KG1a cells expressed no detectable Par-4 protein, whereas Jurkat cells displayed high Par-4 level ( Figure 6A). Hence, KG1a cells were stably transfected by a plasmid containing the full-length Par-4 cDNA sequence.…”

Section: Pkc Regulation By Par-4 Proteinmentioning

confidence: 99%

Role of protein kinase C ζ isoform in Fas resistance of immature myeloid KG1a leukemic cells

Thonel

Bettaı̈eb

Jean

et al. 2001

Blood

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Leukemic CD34 ؉ immature acute myeloid leukemia (AML) cells express Fas receptor but are frequently resistant to Fas agonistic reagents. Fas plays an important role in T-cell-mediated cytotoxicity, and recently it has been suggested that altered Fas signaling may contribute to drug resistance. Therefore, Fas resistance could be one of the mechanisms by which AML progenitors escape chemotherapy or T-cell-based immune intervention. However, the molecular mechanism of Fas resistance in AML cells has not been identified. Fas signaling can be interrupted at 3 mains levels: Fas clustering, alteration of death-inducing-signalingcomplex (DISC) formation, and effector caspase inhibition of downstream caspase-8. This study shows that in the Fas-resistant CD34 ؉ CD38 ؊ KG1a cells, Fas agonists resulted in Fas aggregation but not in caspase-8 activation, related to a defect in DISC formation. However, pretreatment with chelerythrin, but not with calphostin C, resulted in the restoration of Fas-induced caspase-8 activation and cytotoxicity, suggesting that some atypical protein kinase C (PKC) isoforms contributed to the lack of DISC formation. Indeed, treatment with antisense oligonucleotides directed against PKC and enforced expression of Par-4, a negative regulator of PKC activity, restored Fasinduced caspase-8 activity and apoptosis. Moreover, it was found that PKC interacts with FADD and that PKC immunoextracts prepared from KG1a cells are able to phosphorylate FADD in vitro, whereas this phosphorylation is dramatically reduced in Par-4 transfectant cells. IntroductionFas (APO-1/CD95) is a 45-kd membrane protein that belongs to the tumor necrosis factor (TNF)-nerve growth factor receptor family, a group of type 1 transmembrane receptors. 1 Mutational analysis of Fas and the human TNF receptor (TNFR-1) proteins demonstrates that the cytoplasmic domains share a homologous region necessary to transduce the apoptotic signal. This conserved region of approximately 70 amino acids was, therefore, designated as the death domain (DD). The only known physiological ligand of Fas, Fas-L (CD95L), belongs to the family of TNF-related cytokines. 2 Fas-L is synthesized as a transmembrane molecule, and soluble Fas-L trimers can be generated through processing by a metalloprotease. 3,4 Engagement of Fas by agonistic anti-Fas antibodies or by Fas-L triggers apoptosis in a variety of cell types. However, only membrane-bound or multimerized Fas-L induces cell death. 3,4 Moreover, ligand-dependent activation of Fas death pathway requires the oligomerization of Fas receptor, but ligand-independent activation can occur on Fas aggregation induced by Fas overexpression or treatment with anticancer drugs or radiation. [5][6][7][8][9] Clustering of Fas recruits Fas-associated death domain (FADD)-containing protein, which is a bipartite molecule with a death effector domain (DED) at the amino terminus and a DD at the carboxyl terminus. FADD binds to Fas through a DD-DD interaction and recruits the DED-containing procaspase-8 through a DED-DED inter...

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“…Some form of apoptosis may contribute to the pathogenesis of disease in motor neurons (MNs) in people with amyotrophic lateral sclerosis (ALS) (Martin, 1999;Mattson et al, 1999;Sathasivam et al, 2001;Waldmeier, 2003). Apoptosis is an organized form of cell death that eliminates superfluous cells normally during development (Glücksmann, 1951;Oppenheim, 1991), or damaged cells after injury or aberrant replication/repair (Rich et al, 2000), and is mediated by active, intrinsic mechanisms (Danial and Korsmeyer, 2004).…”

Section: Introductionmentioning

confidence: 99%

Adult Motor Neuron Apoptosis Is Mediated by Nitric Oxide and Fas Death Receptor Linked by DNA Damage and p53 Activation

Martin¹,

Chen²,

Liu³

2005

J. Neurosci.

137

163

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Par-4: An Emerging Pivotal Player in Neuronal Apoptosis and Neurodegenerative Disorders

Cited by 60 publications

References 34 publications

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Role of protein kinase C ζ isoform in Fas resistance of immature myeloid KG1a leukemic cells

Adult Motor Neuron Apoptosis Is Mediated by Nitric Oxide and Fas Death Receptor Linked by DNA Damage and p53 Activation

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