The Role of Protein Persulfidation in Brain Aging and Neurodegeneration

Hydrogen sulfide (H2S), originally considered a toxic gas, is now a recognized gasotransmitter. Numerous studies have revealed the role of H2S as a redox signaling molecule that controls important physiological/pathophysiological functions. The underlying mechanism postulated to serve as an explanation of these effects is protein persulfidation (P-SSH, also known as S-sulfhydration), an oxidative posttranslational modification of cysteine thiols. Protein persulfidation has remained understudied due to its instability and chemical reactivity similar to other cysteine modifications, making it very difficult to selectively label. Recent developments of persulfide labeling techniques have started unraveling the role of this modification in (patho)physiology. PSSH levels are important for the cellular defense against oxidative injury, albeit they decrease with aging, leaving proteins vulnerable to oxidative damage. Aging is one of the main risk factors for many neurodegenerative diseases. Persulfidation has been shown to be dysregulated in Parkinson's, Alzheimer's, Huntington's disease, and Spinocerebellar ataxia 3. This article reviews the latest discoveries that link protein persulfidation, aging and neurodegeneration, and provides future directions for this research field that could result in development of targeted drug design

Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response

From PLOS via Jisc Publications RouterHistory: received 2020-06-02, accepted 2021-04-27, collection 2021-06, epub 2021-06-01Publication status: PublishedFunder: Medical Research Council; funder-id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N008707/1Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research; funder-id: http://dx.doi.org/10.13039/501100000849; Grant(s): NC/P002390/1Funder: Fundação para a Ciência e a Tecnologia; funder-id: http://dx.doi.org/10.13039/501100001871; Grant(s): SFRH/BPD/96176/201Funder: Fundação para a Ciência e a Tecnologia; funder-id: http://dx.doi.org/10.13039/501100001871; Grant(s): IF/00735/2014Funder: deutsche forschungsgemeinschaft; Grant(s): CRC/TRR 124Funder: Fondation de l'Avenir pour la Recherche Médicale Appliquée; funder-id: http://dx.doi.org/10.13039/100007380Aspergillus fumigatus is a human fungal pathogen that can cause devastating pulmonary infections, termed “aspergilloses,” in individuals suffering immune imbalances or underlying lung conditions. As rapid adaptation to stress is crucial for the outcome of the host–pathogen interplay, here we investigated the role of the versatile posttranslational modification (PTM) persulfidation for both fungal virulence and antifungal host defense. We show that an A. fumigatus mutant with low persulfidation levels is more susceptible to host-mediated killing and displays reduced virulence in murine models of infection. Additionally, we found that a single nucleotide polymorphism (SNP) in the human gene encoding cystathionine γ-lyase (CTH) causes a reduction in cellular persulfidation and correlates with a predisposition of hematopoietic stem cell transplant recipients to invasive pulmonary aspergillosis (IPA), as correct levels of persulfidation are required for optimal antifungal activity of recipients’ lung resident host cells. Importantly, the levels of host persulfidation determine the levels of fungal persulfidation, ultimately reflecting a host–pathogen functional correlation and highlighting a potential new therapeutic target for the treatment of aspergillosis

Radiation-induced HPA axis activation is associated with up-regulation of pro-inflammatory cytokines in rat brain

34th Congress of the Federation-of-European-Biochemical-Societies, Jul 04-09, 2009, Prague, Czech Republi

Effect of acute stress on NTPDase and 5 -nucleotidase activities in brain synaptosomes in different stages of development

The aim of the present study was to examine the effect of acute restraint stress on rat brain synaptosomal plasma membrane (SPM) ecto-nucleotidase activities at specific stages of postnatal development (15-, 30-, 60- and 90-day-old rats) by measuring the rates of ATP, ADP and AMP hydrolysis 1,24 and 72 h post-stress. At 1 h after stress NTPDase and ecto-5-nucleotidase activities were decreased in rats aged up to 60 days old. In adult rats elevated enzyme activities were detected, which indicated the existence of different short-term stress responses during development. A similar pattern of ATP and ADP hydrolysis changes as well as the ATP/ADP ratio in all developmental stages indicated that NTPDase3 was acutely affected after stress. The long-term effect of acute stress on NTPDase activity differed during postnatal development. In juvenile animals (15 days old) NTPDase activity was not altered. However, in later developmental stages (30 and 60 days old rats) NTPDase activity decreased and persisted for 72 h post-stress. In adult rats only ATP hydrolysis was decreased after 24 h, indicating that ecto-ATPase was affected by stress. Ecto-5-nucleotidase hydrolysing activity was decreased within 24 h in adult rats, while in 15- and 30-day old rats it decreased 72 h post-stress. At equivalent times in pubertal rats (60 days old) a slight activation of ecto-5-nucleotidase was detected. Our results highlight the developmental-dependence of brain ecto-nucleotidase susceptibility to acute stress and the likely existence of different mechanisms involved in time-dependent ecto-nucleotidase activity modulation following stress exposure. Clearly there are differences in the response of the purinergic system to acute restraint stress between young and adult rats. (C) 2009 ISDN. Published by Elsevier Ltd. All rights reserved

17beta-estradiol binding to synaptosomal mitochondria isolated from rat brain nucleus caudatus, hippocampus and brain steam

34th Congress of the Federation-of-European-Biochemical-Societies, Jul 04-09, 2009, Prague, Czech Republi

Effects of acute gamma-irradiation on extracellular adenine nucleotide hydrolysis in developing rat brain

Cell membrane is highly sensitive to irradiation which, acting directly or indirectly, may disturb functions of constitutive proteins including membrane enzymes. Plasma membrane surface-located enzyme chain of ecto-nucleotide triphospho diphosphohydrolases (NTPDases) and 5-nucleotidase are involved in termination of cell purinergic signalization by hydrolyzing extracellular, excitatory adenosine triphosphate (ATP), as well as nucleotide di-, and mono-phosphate (ADP and AMP) to neuroprotective adenosine. Extracellular ATP, ADP, and AMP hydrolyzes were examined in purified synaptic plasma membranes after whole-body acute irradiation. All measurements were done 24 h after irradiation of developing (15-, 30-day-old) and adult (90-day-old) rats with low (50 cGy) and high (2 Gy) dose of gamma-rays. Both, high and low doses inhibited nucleotide hydrolyses in 15-day-old rats; in 30-day-old rats low dose of radiation inhibited ADP and AMP hydrolyses while high dose inhibited only ATP hydrolyse. In adult rats high dose induced no effects, while low dose stimulated nucleotides hydrolyses. According to obtained results it was concluded that ecto-nucleotidases of young rats are more sensitive to irradiation, since even low dose induces inhibition of ecto-nucleotidases activities. Ionizing radiation, by decreasing brain nucleotide hydrolyses in developing rats, induces accumulation of ATP and decreases production of adenosine in synaptic cleft which could be neurocytotoxic. On the contrary, in adult rats low dose of radiation stimulates NTPDase and 5-nucleotidase activity and protective adenosine production which indicates protective and adaptive mechanisms developed in adult brain neuronal cells.9th International Conference on Fundamental and Applied Aspects of Physical Chemistry, Sep 24-26, 2008, Belgrade, Serbi

Kinetic characterization of ecto-nucleoside triphosphate diphosphohydrolases in brain nerve terminals during rat postnatal development

A family of enzymes named ecto-nucleoside triphosphate diphosphohydrolase (NTPDases) catalyzes the termination of ATP and ADP actions. Three different NTPDases (NTPDase 1-3), differing in their preference for a substrate, have been localized in the brain of adult mammals. The goal of our study was to clarify ATP and ADP hydrolyzing activities and kinetic parameters of NTPDases in synaptic plasma membranes (SPM) isolated from 15-, 30-, 60- and 90-days-old female rat brains. ATP and ADP hydrolysis were maximal in the presence of Mg(2+) and showed insensitivity to ion-transporting ATPase inhibitors. The pronounced increase in both, ATP and ADP hydrolysis, were found in the SPM isolated from rats in the first month of life, stayed at the same level in the second month, and then decreased in adulthood. Kinetic analysis are also developmental-dependent, and together with the rate of ATP:ADP hydrolysis, point that all three NTPDases are present in SPM isolated from different developmental stages, with different, developmental-dependent proportion of activities. The lowest velocity and the highest affinity were observed for ATP hydrolyses, while the highest velocity and lowest affinity were detected for ADP hydrolyses in SPM isolated from 15-day old rats. Since specific ATP and ADP hydrolysis were lowest in this stage, we concluded that velocity is crucial for ATPase-, while affinity is for ADPase-part of NTPDases. Increased NTPDases activities, changes in their hydrolysis velocity and substrates affinities during rat postnatal development indicate involvement of adenine nucleotides in processes implicated to neuronal maturation and augmented neuroprotection

Inhibition of Mitochondrial Na-Dependent Ca2+ Efflux from Rat Brain Stem By 17 Beta-Estradiol

The role of membrane-bound estradiol in modulation of mitochondrial Ca2+ flux in nerve endings isolated from rat brain stem was examined. Physiological concentrations of 17 beta-estradiol bind specifically to isolated mitochondria (Bmax 33.8 +/- 2.5 fmoles estradiol/mg of protein, Km 0.185 +/- 0.006 nmoles/l free estradiol). At concentrations ranging from 1 x 10-10 to 2 x 10-9 moles/l, estradiol significantly (by 23-28%) decreases mitochondrial Na-dependent calcium efflux. Decreased calcium efflux was associated with increased affinity of the Na+/Ca2+ exchanger for Na+ and decreased capacity of the exchanger to extrude Ca2+. Calcium ion efflux modulation and mitochondrial ion retention may be the way that 17 beta-estradiol exerts its role in nerve cell homeostasis

Effect of EDTA on copper-induced inhibition of rat myometrial ecto-ATPase activity

The aim of this study was to examine in vitro chelators ability to prevent copper-induced inhibition of rat myometrial ecto-ATPase activity. The effects of increasing CuSO(4) concentrations, in the absence and presence of 1 mmol/l EDTA, showed sigmoidal and complete inhibition relative to the control enzyme activity. IC(50) values, 1.15 x 10(-4) and 1.71 x 10(-3) mol/l in the absence and presence of EDTA, respectively, were determined by Hill analysis from experimental curves. According to the results presented in this work, 1 mmol/l EDTA increased by one order of magnitude CuSO(4) concentration for half-maximal inhibition (IC(50)), by decreasing Cu(2+) concentrations, available to form inactive CuATP(2-) complex.9th International Conference on Fundamental and Applied Aspects of Physical Chemistry, Sep 24-26, 2008, Belgrade, Serbi

Radiation-induced HPA axis activation is associated with up-regulation of pro-inflammatory cytokines in rat brain

34th Congress of the Federation-of-European-Biochemical-Societies, Jul 04-09, 2009, Prague, Czech Republi