Biomedical subjects

A Salminen

Publications and source records attributed to A Salminen.

At least 37 records · Page 2Linked to original sources

PubMed2000

Expression of transcriptional repressor proteins mSin3A and 3B during aging and replicative senescence.

Sin3 proteins have a key role in transcriptional repression mediated by histone deacetylation. Mammalian Sin3 proteins, mSin3A and 3B, act as adapter molecules which bind both to repressive transcription factors and to the methyl-CpG-binding proteins (MeCPs) and recruit histone deacetylases to assemble a multiprotein repressor complex. We have recently observed (Biochem. Biophys. Res. Commun. 252, 274-277, 1998) that the expression of mSin3A but not mSin3B protein is induced during neuronal apoptosis. The purpose of this study was to find out whether aging and replicative senescence affect the expression levels of mSin3A and 3B repressor proteins. We studied the expression levels of mSin3A and 3B mRNAs and proteins both in replicative senescence model of WI-38 fibroblasts and in liver and brain tissues of young (4-6 months) and old (26-30 months) male Wistar rats. Replicative senescence of human WI-38 fibroblasts did not affect the expression levels of mSin3A and 3B mRNAs. However, the late passage WI-38 fibroblasts showed a significant decline in the expression level of mSin3A protein. Immortalization of WI-38 fibroblasts with SV-40 transformation increased the expression level of 6.0 kb mSin3A mRNA. Aging of Wistar rats did not affect the expression levels of either mSin3A or mSin3B mRNAs in the liver and frontal cortex. Similarly, the protein levels of mSin3A and 3B were unaffected in the hippocampus, cerebellum and liver tissues during aging. These results show that aging in vivo, in contrast to replicative senescence, does not affect the expression levels of mSin3A and 3B repressor proteins. However, this does not exclude the possible age-related functional changes mediated by mSin3-histone deacetylase complexes.

Animals↗

PubMed2000

Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells.

L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives.

Animals↗

PubMed2000

A differential display protocol to identify differentially expressed mRNAs in potassium-deprived cerebellar granule cells.

Differential display (DD) has become a popular technique for the identification of differentially expressed genes. Here we present a DD protocol for studying mRNA expression changes during neuronal apoptosis. Neuronal apoptosis is typically dependent on macromolecular synthesis, thus suggesting that regulation of gene expression is involved in control of the activation of the cell-death machinery. In order to identify some of the genes involved, we employed the widely used cell culture model in which apoptosis is induced in rat cerebellar granule cells (CGCs) using potassium deprivation. Although DD has been applied productively in the study of various biological phenomena, the method has its drawbacks. In particular, the cloning and verification of cDNA fragments is frequently described as problematic or laborious, and often produces many "false positives". Here we report the successful use of DD including an efficient protocol for cDNA clone screening and verification. This protocol avoids some of the problems presented by heterogeneous DD bands, which may be a major cause of false-positive results. To identify the desired clones, we apply single-stranded conformational polymorphism (SSCP) and slot blot techniques.

Animals↗

PubMed2000

Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Engineering a new magnesium binding site in the subunit contact region of Escherichia coli inorganic pyrophosphatase.

Three Gln-80 residues belonging to different subunits of homohexameric Escherichia coli pyrophosphatase are separated by only one water molecule to which they are hydrogen bonded. Substitution of Glu for Gln-80 stabilizes quaternary structure of the enzyme but has only a small effect on enzyme activity. The substitution stimulates Mg2+ binding and changes the appearance of the Mg2+ concentration dependence of the rate constant for the trimer --> hexamer transition. These data suggest that a new Mg2+ binding site is formed in the intersubunit contact region as a result of the substitution. Three-dimensional modeling of the mutated protein showed that a chelate complex might form involving two of the three Glu-80 residues.

Amino Acid Substitution↗

PubMed1999

Reciprocal effects of substitutions at the subunit interfaces in hexameric pyrophosphatase of Escherichia coli. Dimeric and monomeric forms of the enzyme.

A homohexameric molecule of Escherichia coli pyrophosphatase is arranged as a dimer of trimers, with an active site present in each of its six monomers. Earlier we reported that substitution of His(136) and His(140) in the intertrimeric subunit interface splits the molecule into active trimers (Velichko, I. S., Mikalahti, K., Kasho, V. N., Dudarenkov, V. Y., Hyytiä, T., Goldman, A., Cooperman, B. S., Lahti, R., and Baykov, A. A. (1998) Biochemistry 37, 734-740). Here we demonstrate that additional substitutions of Tyr(77) and Gln(80) in the intratrimeric interface give rise to moderately active dimers or virtually inactive monomers, depending on pH, temperature, and Mg(2+) concentration. Successive dissociation of the hexamer into trimers, dimers, and monomers progressively decreases the catalytic efficiency (by 10(6)-fold in total), and conversion of a trimer into dimer decreases the affinity of one of the essential Mg(2+)-binding sites/monomer. Disruptive substitutions predominantly in the intratrimeric interface stabilize the intertrimeric interface and vice versa, suggesting that the optimal intratrimeric interaction is not compatible with the optimal intertrimeric interaction. Because of the resulting "conformational strain," hexameric wild-type structure appears to be preformed to bind substrate. A hexameric triple variant substituted at Tyr(77), Gln(80), and His(136) exhibits positive cooperativity in catalysis, consistent with this model.

Amino Acid Substitution↗

PubMed1999

Regulation of PTEN expression in neuronal apoptosis.

PTEN phosphatase is a tumor suppressor gene that dephosphorylates phosphatidylinositol phosphates. PTEN restrains the function of a major antiapoptotic and survival pathway involving phosphoinositide 3-kinase and Akt kinase. Our purpose was to find out whether apoptotic inducers affect the expression of PTEN in cerebellar granule neurons and neuroblastoma 2a cells (Neuro-2a). PTEN mRNA expression showed a major 5.5-kb and a lower abundance 2.5-kb transcripts. In Neuro-2a cells, serum withdrawal induced a prominent, continuous decrease both in 5.5- and 2.5-kb transcripts of PTEN mRNA. Simultaneously, the expression level of 56-kDa PTEN protein decreased in Neuro-2a cells. The decrease in PTEN expression precedes apoptotic changes observed after serum withdrawal. On the contrary, okadaic acid and etoposide only slightly affected the expression of PTEN although they induce a prominent apoptosis in Neuro-2a cells. In cerebellar granule neurons, okadaic acid treatment induced a prominent increase in PTEN mRNA expression after 6-h treatment, both at the 5.5- and 2.5-kb transcripts. The early response in PTEN mRNA expression disappeared in 5.5-kb transcripts already at 12 h and in the case of 2.5-kb transcripts it lasted up to 24 h. Potassium deprivation, known to induce apoptosis in cerebellar granule cells, did not affect PTEN mRNA expression but together with serum deprivation induced a clear decrease in the 5. 5-kb PTEN transcripts. It seems that the changes in PTEN expression level and neuronal apoptosis are not related to each other in general but the expression of PTEN phosphatase seems to regulate certain apoptotic signals affecting phosphoinositide 3-kinase function.

Animals↗

PubMed1999

Evolutionary aspects of inorganic pyrophosphatase.

Based on the primary structure, soluble inorganic pyrophosphatases can be divided into two families which exhibit no sequence similarity to each other. Family I, comprising most of the known pyrophosphatase sequences, can be further divided into prokaryotic, plant and animal/fungal pyrophosphatases. Interestingly, plant pyrophosphatases bear a closer similarity to prokaryotic than to animal/fungal pyrophosphatases. Only 17 residues are conserved in all 37 pyrophosphatases of family I and remarkably, 15 of these residues are located at the active site. Subunit interface residues are conserved in animal/fungal but not in prokaryotic pyrophosphatases.

Amino Acid Sequence↗

PubMed1999

Attenuation of NF-kappaB signaling response to UVB light during cellular senescence.

The ability of cells to adapt to environmental stresses undergoes a progressive reduction during aging. NF-kappaB-mediated signaling is a major defensive system against various environmental challenges. The aim of this study was to find out whether replicative senescence affects the response of the NF-kappaB signaling pathway to UVB light in human WI-38 and IMR-90 fibroblasts. The exposure of early passage fibroblasts to UVB light inhibited the proliferation and induced a flat phenotype similar to that observed in replicatively senescent fibroblasts not exposed to UVB light. The UVB radiation dose used (153 mJ/cm2) did not induce apoptosis in either early or late passage WI-38 fibroblasts. UVB exposure induced a prominent activation of the NF-kappaB signaling pathway both in early and in late passage WI-38 and IMR-90 fibroblasts. Interestingly, the response to UVB light was significantly attenuated in late passage fibroblasts. This attenuation was most prominent in DNA binding activities of nuclear NF-kappaB complexes. Similar senescence-related attenuation was also observed in the DNA binding activities of nuclear AP-1 and Sp-1 factors after UVB treatment. Immunoblotting and -cytochemistry showed an increase in nuclear localization of p50 and p65 components of NF-kappaB complexes. Supershift experiments showed that the specific NF-kappaB complexes contain p50 and p65 protein components but not p52 and c-Rel proteins. Cytoplasmic IkappaBalpha showed a marked decrease at protein level but an increase in phosphorylation after UVB treatment. Transient transfection assays with TK5-CAT and TK10-CAT plasmids carrying NF-kappaB-responsive sites of the TNFalpha promoter were used to analyze the functional activity of the NF-kappaB complexes. Results showed that UVB exposure induced an increase in NF-kappaB-driven CAT expression both in early and in late passage fibroblasts though the response was significantly stronger in early passage fibroblasts. Our results show that the induction of NF-kappaB-mediated signaling by UVB light is highly attenuated in senescent fibroblasts. This attenuation may reduce the stress resistance during cellular senescence.

Benzoquinones↗

PubMed1999

Directed mutagenesis studies of the metal binding site at the subunit interface of Escherichia coli inorganic pyrophosphatase.

Recent crystallographic studies on Escherichia coli inorganic pyrophosphatase (E-PPase) have identified three Mg2+ ions/enzyme hexamer in water-filled cavities formed by Asn24, Ala25, and Asp26 at the trimer-trimer interface (Kankare, J., Salminen, T., Lahti, R., Cooperman, B., Baykov, A. A., and Goldman, A. (1996) Biochemistry 35, 4670-4677). Here we show that D26S and D26N substitutions decrease the stoichiometry of tight Mg2+ binding to E-PPase by approximately 0.5 mol/mol monomer and increase hexamer stability in acidic medium. Mg2+ markedly decelerates the dissociation of enzyme hexamer into trimers at pH 5.0 and accelerates hexamer formation from trimers at pH 7.2 with wild type E-PPase and the N24D variant, in contrast to the D26S and D26N variants, when little or no effect is seen. The catalytic parameters describing the dependences of enzyme activity on substrate and Mg2+ concentrations are of the same magnitude for wild type E-PPase and the three variants. The affinity of the intertrimer site for Mg2+ at pH 7.2 is intermediate between those of two Mg2+ binding sites found in the E-PPase active site. It is concluded that the metal ion binding site found at the trimer-trimer interface of E-PPase is a high affinity site whose occupancy by Mg2+ greatly stabilizes the enzyme hexamer but has little effect on catalysis.

Binding Sites↗

PubMed1999

Distinct mechanisms underlay DNA disintegration during apoptosis induced by genotoxic and nongenotoxic agents in neuroblastoma cells.

Exposure of mouse NB-2a neuroblastoma cells to genotoxic (etoposide or cytosine arabinoside) or nongenotoxic challenges (serum deprivation or okadaic acid) resulted in progressive cell death with biochemical and morphological characteristics typical of apoptosis. Apoptotic cell death induced by nongenotoxic agents was associated with the disintegration of nuclear DNA into high molecular weight (HMW) and oligonucleosomal-DNA fragments, while the formation of HMW-DNA fragments, but not oligonucleosomal-DNA ladder accompanied apoptosis induced by genotoxic agents. Combination of genotoxic and nongenotoxic insults, i.e. incubation of etoposide-treated cells in the serum-free medium, resulted in an additive effect on the profile of DNA disintegration, which involved both HMW fragmentation pattern as in etoposide alone treated cells and the oligonucleosomal-DNA ladder observed with serum-deprived cells. On the other hand, incubation of serum-deprived cells in the presence of Zn2+-ions led to the abrogation of internucleosomal DNA fragmentation but accumulation of HMW-DNA fragments. Differences in the pattern of DNA fragmentation were reproducible in a cell free apoptotic system after treatment of isolated normal nuclei with cytosolic extracts prepared from the cells treated with genotoxic or nogenotoxic apoptotic inducers. Cell free experiments also revealed that activities responsible for the formation of HMW- and oligonucleosomal-DNA fragments are separable in cytosolic extract prepared from the serum-deprived cells. Finally, DNA fragmentation induced by nongenotoxic apoptotic inducers was effectively prevented by cycloheximide and suramin, while both cycloheximide and suramin had only a slight inhibitory effect on DNA fragmentation induced by genotoxic agents. The results presented suggest that distinct pathways underlay disintegration of nuclear DNA during apoptosis induced by genotoxic and nongenotoxic inducers, and that the formation of HMW- and oligonucleosomal-DNA fragments proceeds via separate mechanisms in NB-2a neuroblastoma cells.

Animals↗

PubMed1999

Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite.

Clodronate (dichloromethylidene-bisphosphonate), a halogen-containing bisphosphonate, can inhibit the release of cytokines from RAW 264 macrophages and has anti-inflammatory properties in rheumatoid arthritis, whilst amino-containing bisphosphonates such as alendronate (4-amino-1-hydroxybutylidene-bisphosphonate), have pro-inflammatory properties and can cause an acute phase response. The basis for these pharmacological properties is unclear. Recently, it was demonstrated that clodronate is metabolised by certain cell lines in vitro to an analogue of ATP, whereas amino-bisphosphonates are not. We therefore investigated whether clodronate can also be metabolised by RAW 264 macrophages and whether intracellular accumulation of the metabolite (AppCCl2p) could account for the anti-inflammatory properties of clodronate. The effect of alendronate and AppCCl2p on the release of cytokines (IL-1beta, IL-6, and TNFalpha) from RAW 264 cells was compared, and the effect of the bisphosphonates and AppCCl2p on the DNA binding activities of transcription factors, NF-kappaB and AP-1, was investigated. Pretreatment of RAW 264 macrophages with alendronate augmented the LPS-stimulated release of IL-1beta and increased the binding of NF-kappaB to DNA in an electrophoretic mobility shift assay. Without LPS-induction, alendronate did not affect cytokine release or NF-kappaB binding. Clodronate was metabolised by RAW 264 cells to AppCCl2p. Like clodronate, AppCCl2p inhibited the LPS-induced release of cytokines and NO from RAW 264 macrophages. Both clodronate and its metabolite also inhibited the LPS-stimulated binding of NF-kappaB to DNA. In conclusion, these results suggest that the metabolite of clodronate may be responsible for the anti-inflammatory properties of clodronate, and that the contrasting effects of different bisphosphonates on the release of cytokines could be mediated partly through changes in the DNA binding activity of NF-kappaB.

Alendronate↗

PubMed1999

A rapid and efficient method for preparation of genomic DNA suitable for analysis of both high and low molecular weight DNA fragmentation during neuronal apoptosis.

In this paper, we describe a fast (within 1 h) and efficient method for the preparation of intact genomic DNA suitable for the analysis of DNA integrity in neuronal cells undergoing apoptosis. The procedure involves the embedding of apoptotic cells into low-melting point agarose, in situ cell lysis and purification of DNA samples followed by resolution of fragmented DNA by agarose gel electrophoresis. The method has no restrictions on the number of simultaneous DNA preparations, allows detection of both high and low molecular weight DNA fragments, and is suitable for the preparation of DNA samples from cultured cells, fresh or frozen tissues, as well as from purified nuclei. This procedure is also applicable for the preparation of intact genomic DNA for the megabase-scale analysis.

Animals↗

PubMed1998

Cloning and expression of a unique inorganic pyrophosphatase from Bacillus subtilis: evidence for a new family of enzymes.

An open reading frame located in the COTF-TETB intergenic region of Bacillus subtilis was cloned and expressed in Escherichia coli and shown to encode inorganic pyrophosphatase (PPase). The isolated enzyme is Mn2+-activated, like the authentic PPase isolated from B. subtilis. Although 13 functionally important active site residues are conserved in all 31 soluble PPase sequences so far identified, only two of them are conserved in B. subtilis PPase. This suggests that B. subtilis PPase represents a new family of soluble PPases (a Bs family), putative members of which were found in Archaeoglobus fulgidus, Methanococcus jannaschii, Streptococcus mutans and Streptococcus gordonii.

Amino Acid Sequence↗

PubMed1998

Distinct mode of apoptosis induced by genotoxic agent etoposide and serum withdrawal in neuroblastoma cells.

Here we compared the features of apoptosis induced by DNA-damaging agent, etoposide, and by withdrawal of the growth factors in NB 2a neuroblastoma cells. We showed that serum deprivation and etoposide induced a distinct pattern of regulation of c-Fos, c-Jun and p53 protein levels, as well as the differential changes in DNA-binding activity of AP-1 and NF-kappaB transcription factors. The late phase of apoptesis induced by serum withdrawal was associated with disintegration of nuclear DNA both into high molecular weight (HMW) and oligonucleosomal DNA fragments, whereas etoposide induced the formation of HMW-DNA fragments without internucleosomal DNA cleavage. Incubation of etoposide-treated cells without serum resulted in an additive effect on the pattern of DNA fragmentation. Differences in DNA fragmentation profiles induced by serum withdrawal and etoposide in NB 2a cells were reproducible in nonproliferating cerebellar granule cells and also in a cell free system assay after treatment of isolated normal nuclei with cytosolic extracts prepared from serum-deprived or etoposide-treated cells. Both HMW and oligonucleosomal DNA fragmentation in serum-deprived cells was inhibited by aurintricarboxylic acid and was completely abrogated by cycloheximide. In contrast, DNA fragmentation in etoposide-treated cells was insensitive to the inhibitory effect of aurintricarboxylic acid, and was not prevented by cycloheximide. Our results indicate that in NB 2a neuroblastoma cells etoposide and serum withdrawal induce a distinct mode of apoptosis which is associated with a distinct pattern of regulation of immediately early response genes in the early phase, and with recruitment of different mechanisms for DNA disintegration in the late phase of apoptosis.

Animals↗

PubMed1998

Expression of seizure-related PTZ-17 is induced by potassium deprivation in cerebellar granule cells.

The aim of this study was to identify changes in gene expression during neuronal apoptosis using the differential display (DD) technique. Potassium deprivation was used to induce neuronal apoptosis in cultured rat cerebellar granule cells. DD analysis of about 1600 transcripts resulted in 8 cDNA clones that confirmed differential expression in a slot blot analysis. One of these clones was homologous to the 3' end of seizure-related PTZ-17 RNA. Northern blot analysis showed a marked upregulation of a 2.2 kb RNA 24 hours after potassium withdrawal. This upregulation was prevented by the RNA synthesis inhibitor actinomycin D. The increase in PTZ-17 expression was specific for potassium deprivation induced apoptosis, since the other apoptosis inducers, okadaic acid and staurosporine, did not affect PTZ-17 expression. The level of PTZ-17 RNA was not significantly affected by aging in rat cerebellum. Our data suggest that the upregulation of the PTZ-17 RNA is a part of the steps leading to apoptosis during potassium deprivation in cerebellar granule cells.

Aging↗

PubMed1998

Expression of transcriptional repressor protein mSin3A but not mSin3B is induced during neuronal apoptosis.

mSin3 proteins have an important role in transcriptional repression mediated by histone deacetylation. Our purpose was to find out whether apoptosis affects the expression of mSin3 proteins in neuroblastoma 2a cells. We observed that neuronal apoptosis, induced by serum withdrawal or by treatment with etoposide, okadaic acid or trichostatin A, induced a prominent increase in mSin3A protein expression but did not affect the level of mSin3B protein. Trichostatin A, an inhibitor of histone deacetylases, induced the most prominent upregulation of mSin3A protein. Metabolic labeling and immunoprecipitation of mSin3A showed a marked increase in the synthesis of mSin3A protein in agreement with the immunoblotting results. Interestingly, the expression of mSin3A preceded the activation of caspase-3 and the execution phase of neuronal apoptosis. These results suggest that the expression of mSin3A proteins may provide a regulation mechanism to enhance transcriptional repression or silencing of genes during neuronal apoptosis, as well as during degenerative diseases.

Animals↗

PubMed1998

Neuronal apoptosis induced by histone deacetylase inhibitors.

Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 microM TSA and 1-10 mM butyrate for 1-2 days. Both of these inhibitors induced a prominent neuronal apoptosis characterized by morphological changes as well as by the activation of caspase-3 protease and subsequent cleavage of poly(ADP-ribose) polymerase, one of the caspase-3 targets. Caspase-3 activities reached the highest level on the second day after treatment, higher in the proliferating neuroblastoma cells than in the cerebellar granule neurons. Caspase-3 activation and morphological changes were prevented by cycloheximide treatment. Histone deacetylase inhibitors increased the DNA-binding activities of AP1, CREB and NF-kappaB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells.

Animals↗