Posttranslational Modifications of α-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases.

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential. SIGNIFICANCE STATEMENT: α-Synuclein is a key pathogenic protein in Parkinson's disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in α-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities.

Alpha-Pinene Alleviates Motor Activity in Animal Model of Huntington's Disease via Enhancing Antioxidant Capacity.

Huntington's disease (HD) is a progressive, neurodegenerative, and inherited disease. Antioxidants have been shown to be effective in slowing disease progression in animal models of HD and are under investigation in human clinical trials. α-pinene, a member of the monoterpene class, has been shown to exert antioxidant activity. Therefore, this study aimed to investigate the impact of α-pinene on animal model of HD. Thirty-two male Wistar rats received 3-Nitropropionic acid (3-NP) for induction of the disease model or treated with α-pinene + 3-NP in different groups. Motor skill, and biochemical evaluations to detect oxidant/antioxidant markers in rat cortex and striatum were performed in all groups. We found that α-pinene significantly improved 3-NP-induced changes in the body weight, rotarod activity, time taken to cross the narrow beam, and locomotor activity. Biochemical analysis revealed that α-pinene significantly decreased the 3NP-induced elevation in oxidant markers, nitrite, and malondialdehyde in both cortex and striatum. In addition, α-pinene counteracted the 3-NP-induced fall in antioxidant enzymes, including superoxide dismutase, catalase, and glutathione in the cortex and striatum. In conclusion, we found that α-pinene prevented the motor dysfunction induced by 3-NP in the animal model of Huntington's disease. Oxidants-antioxidant balance might be involved in the protective effect of α-pinene.

An overview of the therapeutic effects of curcumin in reproductive disorders with a focus on the antiinflammatory and immunomodulatory activities.

Curcumin, the polyphenolic compound obtained from turmeric, has several pharmacological properties. These properties include antioxidant, antimicrobial, anti-angiogenic, anticarcinogenic, antiinflammatory, and immunomodulatory activities. Therefore, the clinical efficacy of this substance has been largely investigated for curing numerous disorders. Based on a growing body of literature, this review aimed to investigate curcumin's molecular and clinical effects on reproduction and related disorders. Curcumin in the female reproductive system attenuates folliculogenesis, promotes apoptosis of oocytes and blastocyst, and decreases embryo implantation and survival. Curcumin at <100 mg concentration shows protective effects against testicular injury. The concentration of >250 mg of curcumin exhibits immobilizing action on sperms, and at 500 mg concentration completely blocks pregnancy. Curcumin inhibits vaginal infections, attenuates the severity of the premenstrual syndrome, ameliorates inflammatory conditions in polycystic ovary syndrome, improves preeclampsia, and prevents ectopic endometrial lesions. Taken together, curcumin, because of the numerous biological activities, low level of toxicity, and lower adverse effects compared to the synthetic drugs, could be considered as a protective agent for preserving the semen quality parameters, a contraceptive, and chemotherapeutic or chemopreventive agent, as well as an appropriate agent for the treatment of female reproductive disorders.

Topical phenytoin administration accelerates the healing of acetic acid-induced colitis in rats: evaluation of transforming growth factor-beta, platelet-derived growth factor, and vascular endothelial growth factor.

Ulcerative colitis (UC), limited to the colon's innermost lining, has become a global health problem. Immunomodulatory and monoclonal antibodies are used to treat UC despite their side effects and limitations. Phenytoin is used to heal wounds owing to its effects on growth factors, collagen, and extracellular matrix synthesis. This study aimed to evaluate the effect of topical phenytoin administration in UC. Phenytoin was administered in two doses during the treatment. Eighty male Wistar rats (230-280 g) were divided randomly into ten groups of sham, control, hydrocortisone, phenytoin 1%, and 3% groups in 6- or 12-day treatment protocols. The UC model was induced by the administration of acetic acid 4% into the colon. Animals were killed on the 7th and 13th postoperative days. The main outcome measures included body weight loss, microscopic score, and ulcer index measured using specific criteria. Growth factors were measured by western blotting. Results illustrated that body weight loss was reversed in the treatment groups. Ulcer index had decreased on 6- and 12-day treatment protocols. Microscopic scores in 6-day enema treatment significantly decreased compared to the control groups. Transforming growth factor-beta (TGFß) significantly increased in a time-dependent manner and platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) significantly increased in a time- and dose-dependent manner in phenytoin 1% and 3% in the 6- and 12-day protocols. Phenytoin dose- and time-dependently reversed weight loss. In addition, histopathological parameters included microscopic scores, and the ulcer index was decreased through the induction of growth factors TGFß, PDGF, and VEGF and consequently accelerated ulcer healing.

A Novel Pharmacological Protective Role for Safranal in an Animal Model of Huntington's Disease.

Huntington's disease (HD) is a progressive, neurodegenerative and inherited disease and recent years have witnessed the understanding of the cellular and molecular mechanisms related to HD. Safranal, an organic compound isolated from saffron, has been reported to have anti-apoptotic, anti-inflammatory and antioxidant activity and has studied in chronic and neurodegenerative disease. Therefore, this study was aimed to investigate the effect of safranal on 3-NP induced locomotor activity and biochemical alterations in rats. To this aim, 40 male Wistar rats weighting 250-300 g were divided into 5 groups (n = 8) including sham, 3-NP group (10 mg/kg) as control and treatment groups (3-NP + safranal 0.75, 1.5 and 3 mg/kg) in two weeks duration of treatment. Behavioral/movement assessments in addition to oxidant/antioxidant markers in rat cortex and striatum were evaluated in control and treatment groups. Here, we found that safranal significantly alleviated 3-NP-induced changes of body weight, rotarod activity, number of vacuous chewing movements (VCMs), and locomotor activity. In addition, brain tissue assessments in cortex and striatum revealed that safranal could prevent the elevation of nitrite and malondialdehyde (MDA) levels as well as decrease of superoxide dismutase (SOD), catalase activity and glutathione (GSH) induced by 3-NP. In conclusion our results showed that safranal prevented the motor dysfunction induced by 3-NP in animal model of Huntington's disease. This effect might be due to its modulating effect on oxidants-antioxidant balance.

From the environment to the cells: An overview on pivotal factors which affect spreading and infection in COVID-19 pandemic.

Several factors ranging from environmental risks to the genetics of the virus and that of the hosts, affect the spread of COVID-19. The impact of physicochemical variables on virus vitality and spread should be taken into account in experimental and clinical studies. Another avenue to explore is the effect of diet and its interaction with the immune system on SARS-CoV-2 infection and mortality rate. Past year have witnessed extensive studies on virus and pathophysiology of the COVID-19 disease and the cellular mechanisms of virus spreading. However, our knowledge has not reached a level where we plan an efficient therapeutic approach to prevent the virus entry to the cells or decreasing the spreading and morbidity in severe cases of disease. The risk of infection directly correlates with the control of virus spreading via droplets and aerosol transmission, as well as patient immune system response. A key goal in virus restriction and transmission rate is to understand the physicochemical structure of aerosol and droplet formation, and the parameters that affect the droplet-borne and airborne in different environmental conditions. The lifetime of droplets on different surfaces is described based on the contact angle. Hereby, we recommend regular use of high-quality face masks in high temperature and low humidity conditions. However, in humid and cold weather conditions, wearing gloves and frequently hand washing, gain a higher priority. Additionally, social distancing rules should be respected in all aforementioned conditions. We will also discuss different routes of SARS-CoV-2 entry into the cells and how multiple genetic factors play a role in the spread of the virus. Given the role of environmental and nutritional factors, we discuss and recommend some strategies to prevent the disease and protect the population against COVID-19. Since an effective vaccine can prevent the transmission of communicable diseases and abolish pandemics, we added a brief review of candidate SARS-CoV-2 vaccines.

Trazodone as an Alternative Treatment for Neuroleptic-Associated Akathisia: A Placebo-Controlled, Double-Blind, Clinical Trial.

BACKGROUND: Akathisia is a distressing extrapyramidal complication that follows the use of antipsychotic medications. Early treatment of neuroleptic-associated akathisia (NAA) is of great importance because it may lead to poor therapeutic response and ultimately treatment noncompliance. Considering the lack of adequate response of some patients to conventional treatments and the assumption that serotonin might be involved in the pathophysiology of the disease in addition to dopaminergic mechanisms, we aimed to evaluate the effectiveness of trazodone as an antidepressant agent with strong antagonistic effects on serotonin receptors in the treatment of akathisia. METHODS: In a double-blind clinical trial, 52 patients receiving antipsychotic medications who were diagnosed to have mild to severe NAA using Barnes Akathisia Rating Scale were treated with trazodone 50 mg daily for 5 days and compared with the placebo control group. RESULTS: Patients receiving trazodone did not show a significant difference compared with the control group in terms of the severity of akathisia symptoms until the third day of the study. In contrast, at the end of the fifth day, there was a significant improvement in objective (P = 0.01) and subjective (P = 0.001) symptoms of akathisia and the global clinical assessment of akathisia scale (P = 0.001). Moreover, there was no clear difference between trazodone and placebo group in terms of adverse effects. CONCLUSIONS: Considering the antagonistic effect of trazodone on postsynaptic 5-hydroxytryptamine2A receptors as a possible mechanism of efficacy of this agent in the treatment of NAA, this study suggests that trazodone might be an effective and relatively safe drug.

Discovering the signature of a lupus-related microRNA profile in the Gene Expression Omnibus repository.

Lupus is one of the most prevalent systemic autoimmune diseases. It is a multifactorial disease in which genetic, epigenetic and environmental factors play significant roles. The pathogenesis of lupus is not yet well understood. However, deregulation of microRNAs (miRNAs) - one of the post-transcriptional regulators of genes - can contribute to the development of autoimmune diseases. Over the last two decades, advances in the profiling of miRNA using microarray have received much attention, and it has been demonstrated that miRNAs play a regulatory role in the pathogenesis of lupus. Therefore, dysregulated miRNAs can be considered as promising diagnostic biomarkers for lupus. This article is an overview of lupus-related miRNA profiling studies and arrays in the Gene Expression Omnibus (GEO) database. The aims of our study were to widen current knowledge of known dysregulated miRNAs as potential biomarkers of SLE and to introduce a bioinformatics approach to using microarray data and finding novel miRNA and gene candidates for further study. We identified hsa-miR-4709-5p, hsa-miR-140, hsa-miR-145, hsa-miR-659, hsa-miR-134, hsa-miR-150, hsa-miR-584, hsa-miR-409 and hsa-miR-152 as potential biomarkers by integrated bioinformatics analysis.

Obstacles against the Marketing of Curcumin as a Drug.

Among the extensive public and scientific interest in the use of phytochemicals to prevent or treat human diseases in recent years, natural compounds have been highly investigated to elucidate their therapeutic effect on chronic human diseases including cancer, cardiovascular disease, and neurodegenerative disease. Curcumin, an active principle of the perennial herb Curcuma longa, has attracted an increasing research interest over the last half-century due to its diversity of molecular targets, including transcription factors, enzymes, protein kinases, growth factors, inflammatory cytokines, receptors, and it's interesting pharmacological activities. Despite that, the clinical effectiveness of the native curcumin is weak, owing to its low bioavailability and rapid metabolism. Preclinical data obtained from animal models and phase I clinical studies done in human volunteers confirmed a small amount of intestinal absorption, hepatic first pass effect, and some degree of intestinal metabolism, might explain its poor systemic availability when it is given via the oral route. During the last decade, researchers have attempted with new pharmaceutical methods such as nanoparticles, liposomes, micelles, solid dispersions, emulsions, and microspheres to improve the bioavailability of curcumin. As a result, a significant number of bioavailable curcumin-based formulations were introduced with a varying range of enhanced bioavailability. This manuscript critically reviews the available scientific evidence on the basic and clinical effects and molecular targets of curcumin. We also discuss its pharmacokinetic and problems for marketing curcumin as a drug.

Effect of embryo cryopreservation on derivation efficiency, pluripotency, and differentiation capacity of mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) are pluripotent cells that have the capability for self-renewal. One of the most important factors that affect the efficiency of their isolation is the condition of the mouse embryos. The main objective of this study is to isolate mESCs from C57BL/6 frozen/thawed eight-cell mouse embryos using serum-free culture. We generated mESCs from blastocysts that developed from frozen/thawed embryos of C57BL/6 mice by the 3i + LIF medium. Assessments of the isolated mESC lines (MUKF-1, MUKF-2, and MUKF-3) included simple karyotype analysis; polymerase chain reaction of the testis-determining gene (Sry); determination of alkaline phosphatase (ALP) activity; expressions of pluripotent transcription factors Oct4, Rex1, Sox2, and Nanog by reverse transcription polymerase chain reaction; and immunocytochemistry assessment of OCT4 and SSEA-I expressions at the protein level. We evaluated the ability of these mESC lines to differentiate into three germ layers by embryoid body (EB) formation. The cell doubling time (DT) of isolated mESCs was determined. The 2-C57 cell line was served as control. Germline competence of the male mESC line (MUKF-3) was tested through chimeric mouse production. Three independent mESC lines (MUKF-1, MUKF-2, and MUKF-3) were established from five cryopreserved embryos. The MUKF-1 and MUKF-2 lines were female, whereas MUKF-3 was a male mESC line. Karyotype analysis showed that MUKF-3 had a diploid karyotype, whereas MUKF-1 and MUKF-2 had abnormal karyotypes. All three lines had ALP activity and expressed Oct4, Rex1, and Nanog. Immunocytochemistry assessment for OCT4 and SSEA-I was positive for all three lines. The DT differed in the three mESC lines. MUKF-1 and MUKF-3 could form EB and express developmental genes after spontaneous differentiation. These data demonstrated that probably cryopreservation affected the efficiency of derivation, karyotype, DT, expression of pluripotency, developmental genes, and differentiation capacity of the independent mESC lines.

Effects of cigarette smoke condensate on proliferation and pluripotency gene expression in mouse embryonic stem cells.

BACKGROUND: Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of blastocysts. They can be used as valuable experimental models to test the effects of drugs, chemicals, and environmental contaminants such as cigarette smoke condensate (CSC) on preimplantation embryo development. The aim of this study was to evaluate the effect of CSC on ESCs derived from mice with different genetic backgrounds and maternal ages. METHODS: The study groups consisted of mouse ESCs (mESCs) obtained from three sources: blastocysts developed from fertilized oocytes of two-month-old (2-C57) and six-month-old (6-C57) C57BL/6 inbred mice and those developed from fertilized oocytes of two-month-old (2-NMRI) NMRI outbred mice. The groups of mESCs were exposed to 0.04, 4, and 40 µg/mL CSC. After exposure, we measured cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and real-time polymerase chain reaction for changes in expressions of Oct4, Sox2, Nanog, Ahr, Bax, Bcl2, TFAM, and POLG. The cell doubling time (DT) of these populations was also determined. RESULTS: We observed that CSC changed proliferation and DT in the 2-C57 and 6-C57 cells. There was no change in 2-NMRI cells. Exposure to CSC caused changes in the gene expressions and induced apoptosis in all three cell lines. CONCLUSION: Based on the results of the study, it can be concluded that CSC has an effect on the viability, DT and gene expression patterns in mouse ESCs and its effects vary based on the genetic background and maternal age of isolated mouse ESCs.

Oxidative stress and neuroinflammation in the story of Parkinson's disease: Could targeting these pathways write a good ending?

Although, current medications for Parkinson's disease can control and relief symptoms of the disease efficiently, they are unable to either prevent progression of the disease or maintain their controlling ability as a long-term medication. To find suitable adjuvant and/or alternative treatments, researchers have investigated antioxidative and anti-inflammatory approaches, since emerging evidence consider oxidative stress and neuroinflammation as leading causes of the development of Parkinson's disease. Here, how oxidative stress and neuroinflammation take part in Parkinson's disease pathogenesis was discussed based on featured studies in this context. Then, preclinical and clinical trial studies, which evaluated antioxidative and anti-inflammatory compounds' ability to treat Parkinson's disease, were reviewed.

Protective effect of pioglitazone on morphine-induced neuroinflammation in the rat lumbar spinal cord.

BACKGROUND: Morphine-induced tolerance is associated with the spinal neuroinflammation. The aim of this study was to explore the effects of oral administration of the pioglitazone, the peroxisome proliferator activated receptor gamma (PPAR-γ) agonist, on the morphine-induced neuroinflammation in the lumbar region of the male Wistar rat spinal cord. RESULTS: Co-administration of the pioglitazone with morphine not only attenuated morphine-induced tolerance, but also prevented the up-regulation of pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta, and interleukin 6) and nuclear factor-kappa B activity. Administration of the GW-9662 antagonized the above mentioned effects of the pioglitazone. CONCLUSIONS: It is concluded that oral administration of the pioglitazone attenuates morphine-induced tolerance and the neuroinflammation in the lumbar region of the rat spinal cord. This action of the pioglitazone may be, at least in part, due to an interaction with the spinal pro-inflammatory cytokine expression and the nuclear factor-kappa B activity.

Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms in rats.

BACKGROUND/PURPOSE: Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. In recent years, several studies have been conducted to find agents that can prevent the development of these two phenomena. The aim of the present study is to evaluate the effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on morphine-induced tolerance and withdrawal symptoms. METHODS: Groups of male rats received daily morphine [for induction of tolerance (10 mg/kg) and for induction of dependence (additive doses: 5 mg/kg/12 h, 10 mg/kg/12 h, 15 mg/kg/12 h, 20 mg/kg/12 h, and 25 mg/kg/12 h)] in combination with propylene glycol or simvastatin [5 mg/kg, per os (p.o.), 10 mg/kg, p.o., and 20 mg/kg, p.o.]. Next, the nociception was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. The animals received additional doses of morphine for 9 days in order to induce dependency. One hour after the last dose of the morphine injection, naloxone was administered and withdrawal symptoms were recorded for 1 hour. RESULTS: The results of the present study showed that chronic morphine administration induced tolerance to the analgesic effect for 19 days, whereas simvastatin (20 mg/kg, p.o.) delayed the day of the established tolerance by 5 days. The administration of simvastatin also prevented the morphine-induced shift to the right of the 50% effective dose (ED50) in the dose-response curve. Furthermore, the results showed that simvastatin decreased the total withdrawal score significantly. CONCLUSION: We found that simvastatin attenuated morphine-induced tolerance and withdrawal symptoms.

A new pharmacological role for donepezil: attenuation of morphine-induced tolerance and apoptosis in rat central nervous system.

BACKGROUND: Tolerance to the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration. It has been shown that morphine-induced tolerance is associated with apoptosis in the central nervous system and neuroprotective agents which prevented apoptosis signaling could attenuate tolerance to the analgesic effects. On the other hand donepezil, an acetylcholinesterase inhibitor, has been reported to have neuroprotective effects. Therefore in this study, the effect of systemic administration of donepezil on morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord was evaluated. Various groups of rats received morphine (ip) and different doses of donepezil (0, 0.5, 1, 1.5 mg/kg/day). Nociception was assessed using tail flick apparatus. Tail flick latency was recorded when the rat shook its tail. For apoptosis assay other groups of rats received the above treatment and apoptosis was evaluated by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method. RESULTS: The results showed that administration of donepezil (0.5, 1, 1.5 mg/kg, ip) delayed the morphine tolerance for 9, 12 and 17 days, respectively. Furthermore pretreatment injection of donepezil attenuated the number of apoptotic cells in the cerebral cortex and lumbar spinal cord compared to the control group. CONCLUSION: In conclusion, we found that systemic administration of donepezil attenuated morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord.

Gap junction blockers: a potential approach to attenuate morphine withdrawal symptoms.

BACKGROUND: The exact mechanisms of morphine-induced dependence and withdrawal symptoms remain unclear. In order to identify an agent that can prevent withdrawal syndrome, many studies have been performed. This study was aimed to evaluate the effect of gap junction blockers; carbenoxolone (CBX) or mefloquine (MFQ); on morphine withdrawal symptoms in male rat. Adult male Wistar rats (225 - 275 g) were selected randomly and divided into 10 groups. All groups underwent stereotaxic surgery and in order to induce dependency, morphine was administered subcutaneously) Sc) at an interval of 12 hours for nine continuous days. On the ninth day of the experiment, animals received vehicle or CBX (100, 400, 600 µg/10 µl/rat, icv) or MFQ (50, 100 and 200 µg/10 µl/rat, icv) after the last saline or morphine (Sc) injection. Morphine withdrawal symptoms were precipitated by naloxone hydrochloride 10 min after the treatments. The withdrawal signs including: jumping, rearing, genital grooming, abdomen writhing, wet dog shake and stool weight, were recorded for 60 minutes. RESULTS: Results showed that CBX and MFQ decreased all withdrawal signs; and the analysis indicated that they could attenuate the total withdrawal scores significantly. CONCLUSION: Taking together it is concluded that gap junction blockers prevented naloxone-precipitated withdrawal symptoms.

Molecular mechanism and potential therapeutic targets of necroptosis and ferroptosis in Alzheimer's disease.

Alzheimer's disease (AD), a neurodegenerative condition, is defined by neurofibrillary tangles, amyloid plaques, and gradual cognitive decline. Regardless of the advances in understanding AD's pathogenesis and progression, its causes are still contested, and there are currently no efficient therapies for the illness. The post-mortem analyses revealed widespread neuronal loss in multiple brain regions in AD, evidenced by a decrease in neuronal density and correlated with the disease's progression and cognitive deterioration. AD's neurodegeneration is complicated, and different types of neuronal cell death, alone or in combination, play crucial roles in this process. Recently, the involvement of non-apoptotic programmed cell death in the neurodegenerative mechanisms of AD has received a lot of attention. Aberrant activation of necroptosis and ferroptosis, two newly discovered forms of regulated non-apoptotic cell death, is thought to contribute to neuronal cell death in AD. In this review, we first address the main features of necroptosis and ferroptosis, cellular signaling cascades, and the mechanisms involved in AD pathology. Then, we discuss the latest therapies targeting necroptosis and ferroptosis in AD animal/cell models and human research to provide vital information for AD treatment.

Non-SUMOylated alternative spliced isoforms of alpha-synuclein are more aggregation-prone and toxic.

The exon skipping of α-Synuclein (α-Syn), the main constituent of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD), forms four isoforms. In contrast to the full length α-Syn (α-Syn 140), little is known about the splice isoforms' properties and functions. SUMOylation, a post-translational modification, regulates α-Syn function, aggregation, and degradation, but information about α-Syn isoforms and the effect of SUMOylation on them is unknown. Therefore, this study aims to characterize the SUMOylation of α-Syn isoforms and its impact on cell death and α-Syn aggregation. In a cellular model of PD induced by rotenone, cell toxicity, SUMOylation, and α-Syn aggregation with or without isoforms overexpression were evaluated. First, rotenone induced cell toxicity and α-Syn aggregation, with a significant reduction of SUMOylation and autophagy. Boosting SUMOylation prevented α-Syn aggregation, phosphorylation and recovery of autophagy. Moreover, α-Syn 140 and α-Syn 126 were SUMOylated while the other two isoforms, α-Syn 112 and 98 were not and their overexpression showed that were more toxic and induced more α-Syn aggregation. Rotenone increased their toxicity that was not affected by boosting SUMOylation. These results may indicate a role of SUMOylation in modulating α-Syn aggregation, inducing to understanding more about the behavior of α-Syn isoforms.

Syntaxin-1a and SNAP-25 expression level is increased in the blood samples of ischemic stroke patients.

The interest for the discovery of blood biomarkers for several neurological disorders, including Ischemic Stroke (IS), is growing and their identification in blood samples would be revolutionary allowing a fast and better pathology prediction or outcome and to collect information on patient recovery. The increased permeability of the blood-brain barrier, following a brain infarct, allows the detection of brain proteins in the blood flow. In this work, we analyzed the expression levels of two synaptic proteins Syntaxin (STX)-1a and Synaptosomal Associated Protein, 25 kDa (SNAP-25), in Peripheral Blood Mononuclear Cell (PBMC), serum and in Neuronal Derived Extracellular vesicles (NDEs) of IS patients, age and sex matched healthy control (HC) and younger HC (Y-HC). Interestingly, we identified STX-1a protein in the cytoplasm of PBMC and both STX-1a and SNAP-25 expression levels were significantly augmented in all IS patient's blood fractions compared to control subjects. In addition, STX-1a blood levels correlated with the IS clinical scales National Institutes of Health Stroke Scale (NIH-SS) and the modified Barthel Index (BI). These results prompted us to speculate that STX-1a and SNAP-25 hematic fluctuations depict the brain damage after an ischemic attack and that their hematic detection could represent a novel and accessible IS biomarkers.

Protective Effect of Curcuma Extract in an Ex Vivo Model of Retinal Degeneration via Antioxidant Activity and Targeting the SUMOylation.

Retinal degeneration is the major and principal cause behind many incurable blindness diseases. Several studies indicated the neuroprotective effect of Curcuma longa in eye pathologies, specifically retinopathy. However, the molecular mechanism behind its effect has not been completely elucidated. Using an ex vivo model of retinal degeneration obtained from an ex vivo optic nerve cut (ONC), we demonstrated that Curcuma extract (Cur) exerted a neuroprotective effect. Importantly, Cur was able to modulate apoptosis and MAPK signaling pathway activation and prevent retinal ganglion cell (RGC) loss. Other well-known neuroprotective pharmacological tools, including memantine (Mem), citicoline (Cit), and ginkgolic acid (GA), were used to compare the potential mechanisms of Cur. The antioxidant activity of retinas treated with Cur following optic nerve cut was significantly higher than control, but Cur failed to change the retina glutamate content. Considering the antioxidant effect of Cur and taking advantage of our recent findings on the crosstalk between oxidative stress and post-translational protein modifiers, in particular, small ubiquitin-related modifier (SUMO), we were interested in exploring the effect of Cur on SUMOylation. We found that Cur significantly prevented the increase of protein SUMOylation, confirming our previous in vitro data indicating the cytoprotective effect of curcumin through modulating the oxidative stress and SUMO-JNK axis. Altogether, these results suggest that Curcuma protects the retina from degeneration via antioxidant activity and targets SUMOylation. Therefore, it might be considered for the combination therapy with other neuroprotective agents with different mechanisms in preclinical studies on retinal degeneration.