Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine ß-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy.

Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer's disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine ß-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H2S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H2S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H2S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.

ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.

Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

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.

Aspergillus 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.

POSTERIOR CORTEX SEIZURES - PEDIATRIC CHALLENGES.

Posterior cortex seizures have a complex semiologic presentation that is especially challenging in the pediatric population. Therefore, using clinical presentation in localizing ictal involvement is not sufficient in children, thus making this type of epilepsy quite under-recognized. As most of the ictal symptoms are subjective and could well be overshadowed by symptoms arising from adjacent cortices, primarily temporal and central ones, it is necessary not to overlook this large source of pharmacoresistant epilepsies. The parietal lobe as part of an extensive synaptic network is a great imitator, thus quite often producing inaccurate localization readings on scalp electroencephalography (EEG) due to very scattered interictal discharges and uninformative ictal recordings. Using direct cortical recordings in delineating the epileptogenic zone is helpful in some cases but even highly experienced epileptologists may erroneously interpret some features as arising from other localizations, especially the frontal lobe. Epilepsy surgery from the posterior quadrant is still quite rare and relatively unsuccessful, especially in non-lesional epilepsies due to elaborate mechanisms of connectivity, misleading semiology, and non-localizing EEG recordings, possibly due to insufficiency of parietal cortex synchronicity. Applying the aforementioned to the pediatric age makes it perhaps the most difficult challenge for a pediatric epileptologist.

Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration.

Life on Earth emerged in a hydrogen sulfide (H2S)-rich environment eons ago and with it protein persulfidation mediated by H2S evolved as a signaling mechanism. Protein persulfidation (S-sulfhydration) is a post-translational modification of reactive cysteine residues, which modulate protein structure and/or function. Persulfides are difficult to label and study due to their reactivity and similarity with cysteine. Here, we report a facile strategy for chemoselective persulfide bioconjugation using dimedone-based probes, to achieve highly selective, rapid, and robust persulfide labeling in biological samples with broad utility. Using this method, we show persulfidation is an evolutionarily conserved modification and waves of persulfidation are employed by cells to resolve sulfenylation and prevent irreversible cysteine overoxidation preserving protein function. We report an age-associated decline in persulfidation that is conserved across evolutionary boundaries. Accordingly, dietary or pharmacological interventions to increase persulfidation associate with increased longevity and improved capacity to cope with stress stimuli.