Accumulation Of Misfolded Proteins Research Articles

Shedding light on microglial dysregulation in Alzheimer's disease: exploring molecular mechanisms and therapeutic avenues.

Alzheimer's disease (AD) stands out as the foremost prevalent neurodegenerative disorder, characterized by a complex etiology. Various mechanisms have been proposed to elucidate its onset, encompassing amyloid-beta (Aβ) toxicity, tau hyperphosphorylation, oxidative stress and reactive gliosis. The hallmark of AD comprises Aβ and tau aggregation. These misfolded protein aggregates trigger the activation of glial cells, primarily microglia. Microglial cells serve as a major source of inflammatory mediators and their cytotoxic activation has been implicated in various aspects of AD pathology. Activated microglia can adopt M1 or M2 phenotypes, where M1 promotes inflammation by increasing pro-inflammatory cytokines and M2 suppresses inflammation by boosting anti-inflammatory factors. Overexpressed pro-inflammatory cytokines include interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in adjacent brain regions.Furthermore, microglial signaling pathways dysregulated in AD are myeloid differentiation primary-response protein 88 (Myd 88),colony-stimulating factor-1receptor (CSF1R) anddedicator of cytokinesis 2 (DOCK2), which alter the physiology. Despite numerous findings, the causative role of microglia-mediated neuroinflammation in AD remains elusive. This review concisely explores cellular and molecular mechanisms of activated microglia and their correlation with AD pathogenesis. Additionally, it highlights promising therapeutics targeting microglia modulation, currently undergoing preclinical and clinical studies, for developing effective treatment for AD.

G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.

Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.

The regulation of miRNAs using curcumin and other polyphenols during the prevention and treatment of Alzheimer's disease.

Alzheimer's disease (AD), a prevalent neurodegenerative disorder, predominantly affects individuals over the age of 65 and poses significant challenges in terms of effective management and treatment. The disease's pathogenesis involves complex molecular pathways including misfolded proteins accumulation, neuroinflammation, and synaptic dysfunction. Recent insights have highlighted the role of microRNAs (miRNAs) as critical regulators within these pathways, where they influence gene expression and contribute to the pathophysiological landscape of AD. Notably, emerging research has demonstrated that polyphenols, including curcumin, might modulate miRNA activity, thus offering a novel approach to mitigate AD symptoms and progression. This review explores the potential mechanisms through which polyphenols regulate miRNA expression and activity, specifically focusing on autophagy enhancement and inflammation reduction in the context of AD. We provide a detailed examination of key studies linking miRNA dysregulation to AD pathogenesis and discuss how polyphenols might correct these aberrations. The findings presented here underscore the therapeutic potential of polyphenols in AD treatment via miRNA modulation, pointing to new directions in disease management strategies and highlighting the need for targeted research into miRNA-based interventions.

Integrated physiological, transcriptomics and metabolomics analyses provide insights into thermal stress of razor clam, Sinonovacula constricta

Extreme high temperature is believed as a major inducer to summer mortality syndrome in molluscs, which frequently occurs and has caused serious economic losses. In this study, we elucidated the molecular differences of transcriptomic and metabolomics responses and investigated the mechanisms of response to heat stress in razor clam (Sinonovacula constricta) after exposure to 32 °C lasting for either 24 h or 15 d. Notably, protein processing in endoplasmic reticulum (ER) and glycerophospholipid pathway were obviously enriched, suggesting that maintaining ER and cell membrane homeostasis play an important role for razor clams to response to heat stress. After heat stress for 24 h, fatty acid synthesis-related genes, fasn, far1 and scd5, were repressed, and the contents of fumarate and citrate metabolites and the activities of SDH and CS enzymes in TCA cycle were significantly reduced. By contrast, T-SOD and CAT activities and MDA content were dramatically increased. After heat stress for 15 d, the lipid metabolism-related genes pparα and plb1 were downregulated, and the SDH activity was remarkably decreased. Conversely, the expression of pck1 and odh were upregulated, indicating that heat stress may limit the aerobic capacities of the razor clams. Additionally, T-SOD activity was still higher than that of the control group, while CAT activity and MDA content decreased. These findings suggested that heat stress may inhibit the lipid metabolism and TCA cycle, activate oxidative stress and cause misfolded proteins accumulation which leads to ER stress. This study contributes to understand the potential metabolism mechanisms of S.constricta in response to heat stress.

Mechanism of ropinirole in the treatment of amyotrophic lateral sclerosis

Abstract. Amyotrophic lateral sclerosis (ALS) is now still a rare disease that cannot be cured, so patients are in desperate need of medications that can treat the disease. Until now, many researchers have tried to illustrate the pathogenesis of ALS, including misfolded protein aggregation, oxidative stress damage, etc. At the same time, many drugs are in the research phase. However, no consensus has been reached on the pathogenesis of ALS and the drugs on the market can only slow down the process of ALS. This paper firstly investigated researches on the pathogenesis of ALS, and then investigated the possible mechanism of ropinirole, a drug originally used to treat Parkinsons disease (PD) but promising as a treatment for ALS. Meanwhile, the latest clinical trials of ropinirole were reviewed in this paper, suggesting ropinirole could possibly treat ALS through multiple mechanisms including reducing oxidative stress, inducing autophagy, etc. Through investigation, this paper provides theoretical guidance for future studies on the mechanisms of ropinirole in ALS. However, the pathogenic mechanism of ALS and the therapeutic mechanism of ropinirole are not fully understood, especially the pathway of ropinirole in scavenging ROS and regulating the abnormal metabolism of lipids needs further studies.

Role of autophagy in myocardial remodeling after myocardial infarction.

Autophagy is the process of reusing the body's senescent and damaged cell components, which can be regarded as the cellular circulatory system. There are three distinct forms of autophagy: macro-autophagy, micro-autophagy, and chaperone-mediated autophagy. In the heart, autophagy is regulated mainly through mitophagy due to the metabolic changes of cardiomyocytes caused by ischemia and hypoxia. Myocardial remodeling is characterized by gradual heart enlargement, cardiac dysfunction, and extraordinary molecular changes. Cardiac remodeling after myocardial infarction is almost inevitable, which is the leading cause of heart failure. Autophagy has a protective effect on myocardial remodeling improvement. Autophagy can minimize cardiac remodeling by preventing misfolded protein accumulation and oxidative stress. This review summarizes the nestest molecular mechanisms of autophagy and myocardial remodeling, the protective effects, and the new target of autophagy medicine in cardiac remodeling. The future development and challenges of autophagy in heart disease are also summarized.

Potential Mechanisms of Tunneling Nanotube Formation and Their Role in Pathology Spread in Alzheimer's Disease and Other Proteinopathies.

Alzheimer's disease (AD) is the most common type of dementia worldwide. The etiopathogenesis of this disease remains unknown. Currently, several hypotheses attempt to explain its cause, with the most well-studied being the cholinergic, beta-amyloid (Aβ), and Tau hypotheses. Lately, there has been increasing interest in the role of immunological factors and other proteins such as alpha-synuclein (α-syn) and transactive response DNA-binding protein of 43 kDa (TDP-43). Recent studies emphasize the role of tunneling nanotubes (TNTs) in the spread of pathological proteins within the brains of AD patients. TNTs are small membrane protrusions composed of F-actin that connect non-adjacent cells. Conditions such as pathogen infections, oxidative stress, inflammation, and misfolded protein accumulation lead to the formation of TNTs. These structures have been shown to transport pathological proteins such as Aβ, Tau, α-syn, and TDP-43 between central nervous system (CNS) cells, as confirmed by in vitro studies. Besides their role in spreading pathology, TNTs may also have protective functions. Neurons burdened with α-syn can transfer protein aggregates to glial cells and receive healthy mitochondria, thereby reducing cellular stress associated with α-syn accumulation. Current AD treatments focus on alleviating symptoms, and clinical trials with Aβ-lowering drugs have proven ineffective. Therefore, intensifying research on TNTs could bring scientists closer to a better understanding of AD and the development of effective therapies.

Application of Nanocomposites and Nanoparticles in Treating Neurodegenerative Disorders.

Neurodegenerative diseases represent a formidable global health challenge, affecting millions and imposing substantial burdens on healthcare systems worldwide. Conditions, like Alzheimer's, Parkinson's, and Huntington's diseases, among others, share common characteristics, such as neuronal loss, misfolded protein aggregation, and nervous system dysfunction. One of the major obstacles in treating these diseases is the presence of the blood-brain barrier, limiting the delivery of therapeutic agents to the central nervous system. Nanotechnology offers promising solutions to overcome these challenges. In Alzheimer's disease, NPs loaded with various compounds have shown remarkable promise in preventing amyloid-beta (Aβ) aggregation and reducing neurotoxicity. Parkinson's disease benefits from improved dopamine delivery and neuroprotection. Huntington's disease poses its own set of challenges, but nanotechnology continues to offer innovative solutions. The promising developments in nanoparticle-based interventions for neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), have offered new avenues for effective treatment. Nanotechnology represents a promising frontier in biomedical research, offering tailored solutions to the complex challenges posed by neurodegenerative diseases. While much progress has been made, ongoing research is essential to optimize nanomaterial designs, improve targeting, and ensure biocompatibility and safety. Nanomaterials possess unique properties that make them excellent candidates for targeted drug delivery and neuroprotection. They can effectively bypass the blood-brain barrier, opening doors to precise drug delivery strategies. This review explores the extensive research on nanoparticles (NPs) and nanocomposites in diagnosing and treating neurodegenerative disorders. These nanomaterials exhibit exceptional abilities to target neurodegenerative processes and halt disease progression.

Heat stress-induced decapping of WUSCHEL mRNA enhances stem cell thermotolerance in Arabidopsis

The plasticity of stem cells in response to environmental change is critical for multicellular organisms. Here, we show that MYB3R-like directly activates the key plant stem cell regulator WUSCHEL (WUS) by recruiting the methyltransferase ROOT INITIATION DEFECTIVE 2 (RID2), which functions in m7G methylation at the 5’ cap of WUS mRNA to protect it from degradation. We demonstrated that protein-folding genes are repressed by WUS to maintain precise protein synthesis in stem cells by preventing the reuse of misfolded proteins. However, upon heat stress, the MYB3R-like/RID2 module is repressed to reduce WUS transcripts via the decapping of nascent WUS mRNA. This releases the inhibition of protein folding capacity in stem cells and protects plant stem cells from heat-shock by eliminating misfolded protein aggregation. Our results reveal a tradeoff strategy in plants by reducing the accuracy of protein synthesis in exchange for the survival of stem cells at high temperatures.

Microglial senescence in neurodegeneration: Insights, implications, and therapeutic opportunities.

The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression. Recent research has linked disease-associated microglia to their transition into a senescent state-characterized by irreversible cell cycle arrest-in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets. This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.

MicroRNA 29a alleviates mitochondrial stress in diet-induced NAFLD by inhibiting the MAVS pathway

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder characterized by fat accumulation in the liver. This leads to aggravated hepatocyte inflammation due to impaired mitochondrial function, mitochondrial double-stranded RNA (mt-dsRNA) release, elevated oxidative stress, and reactive oxygen species (ROS) production.MicroRNA-29a (miR-29a) is used to reduce hepatic fibrosis in cases of cholestatic liver damage and lessen the severity of non-alcoholic steatohepatitis in animal studies by influencing mitochondrial protein balance. However, the effectiveness of miR-29a in diminishing mt-dsRNA-induced exacerbation of NAFLD remains poorly understood, particularly in the context of a Western diet (WD). Our results have found that mice with increased miR-29a levels and fed a WD showed notably decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, and low-density lipoprotein cholesterol levels. They also experienced less weight gain and lower final body and liver weights. In addition, overexpression of miR-29a reduced the severity of fibrosis, alleviated hepatic oxidative stress, misfolded protein aggregates, and the release of mt-dsRNA. Moreover, miR-29a attenuated the innate immune mitochondrial antiviral-signaling protein (MAVS) pathway response. In vitro, the research using HepG2 cells confirmed that miR-29a reduces MAVS expression and decreases the release of mt-dsRNA and superoxide initiated by palmitic acid (PA). Analysis of luciferase activity further established that the specific binding of miR-29a to the 3′UTR of MAVS led to a repression of its expression. In conclusion, these groundbreaking findings underscore the potential of miR-29a in improving the treatment of NAFLD and liver steatofibrosis by inhibiting the MAVS signaling pathway.

Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner

ABSTRACT Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis. Abbreviations: AAAs: amino acid analogs; foxo: forkhead box, sub-group O; IFMs: indirect flight muscles; UPS: ubiquitin-proteasome system; USP14: ubiquitin specific peptidase 14

Abstract Tu066: Loss of Sigmar1 Aggravated Cardiac Proteotoxicity and Cardiac Dysfunction in Mutant αB-Crystallin Mouse

Background: Deposition of misfolded protein aggregates observed in diverse cardiac disease models leads to proteotoxic cardiomyopathy. In earlier studies, we confirmed mutations in α-B-Crystallin, specifically Arg120Gly (CryAB R120G ), develop proteotoxic cardiomyopathy. Cardiomyocyte-specific CryAB R120G overexpression leads to cardiac dysfunction resulting from the accumulation of toxic pre-amyloid oligomers and protein aggregation. In the event of proteotoxic insult, the chaperone proteins function to prevent the accumulation of protein aggregates. One of the multitasking chaperone proteins in the heart is Sigmar1, whose role in proteotoxic cardiomyopathy and protein aggregation remains unknown. Hypothesis: We hypothesize that Sigmar1 plays an essential role in protein aggregate clearance, and the absence of Sigmar1 in CryAB R120G mice aggravates pathological cardiac remodeling. Methods and Result: We measured Sigmar1 expression level in CryAB R120G hearts and found a significant reduction in endogenous Sigmar1 protein and transcript levels in CryAB R120G hearts. Co-immunoprecipitation and yeast-two-hybrid assays demonstrated a direct interaction between Sigmar1 and CryAB. Therefore, we evaluated Sigmar1’s function in the proteotoxic model of heart failure. We ablated Sigmar1 in CryAB R120G , expressing myocytes both in vitro by using Sigmar1 siRNA and in vivo by crossing Sigmar1 knockout with CryAB R120G (CryAB R120G xSigmar1 -/- ) . Both i n vitro and in vivo studies displayed a dramatic increase in protein aggregate size and content in CryAB R120G xSigmar1 -/- heart, assessed by immunostaining and electron microscopy. Echocardiography showed age-dependent aggravation of cardiac contractile dysfunction, and Masson’s Trichrome staining showed increased cardiac fibrosis in the CryAB R120G xSigmar1 -/- hearts compared to CryAB R120G hearts. Conclusion: Overall, we found that Sigmar1 directly interacts with CryAB and plays a vital role in the degradation of protein aggregates where the absence of Sigmar1 causes increased protein aggregate size and content in CryAB R120G mice, leading to aggravated pathology with ventricular dysfunction, increased interstitial fibrosis, and cardiac hypertrophy.

Muscle-specific lack of Gfpt1 triggers ER stress to alleviate misfolded protein accumulation.

Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in (KI) mouse model carrying a frameshift variant in Gfpt1 exon 9, simulating that found in a patient with CMS. As Gfpt1 exon 9 is exclusively expressed in striated muscles, Gfpt1-KI mice were deficient for Gfpt1 only in skeletal muscles. In Gfpt1-KI mice, (1) UDP-HexNAc, CMP-NeuAc and protein O-GlcNAcylation were reduced in skeletal muscles; (2) aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures; and (3) markers of the unfolded protein response (UPR) were elevated in skeletal muscles. Denervation-mediated enhancement of endoplasmic reticulum (ER) stress in Gfpt1-KI mice facilitated protein folding, ubiquitin-proteasome degradation and apoptosis, whereas autophagy was not induced and protein aggregates were markedly increased. Lack of autophagy was accounted for by enhanced degradation of FoxO1 by increased Xbp1-s/u proteins. Similarly, in Gfpt1-silenced C2C12 myotubes, ER stress exacerbated protein aggregates and activated apoptosis, but autophagy was attenuated. In both skeletal muscles in Gfpt1-KI mice and Gfpt1-silenced C2C12 myotubes, maladaptive UPR failed to eliminate protein aggregates and provoked apoptosis.

Exploring the anti-amyloid potential of salvianolic acid A against the ALS-associated mutant SOD1: insights from molecular docking and molecular dynamic simulations

ABSTRACT A central feature of a variety of related neurological disorders, including amyotrophic lateral sclerosis (ALS), is the deposition of misfolded protein aggregates in key regions of the human brain. Hence, targeting aggregation-prone SOD1 with small molecules can be used to design strategies to inhibit its aggregation. Based on molecular docking and molecular dynamics (MD) simulation, this study suggested that plant flavonoids can act as a potent anti-amyloidogenic polyphenol against SOD1 aggregation. Initial screening of flavonoids against protein aggregates identified Rosmarinic acid and Salvianolic acid A as promising drug leads that can effectively inhibit pathogenic behaviour. Our results showed that Salvianolic acid A reduces the β-sheet content and increases the structural stability, hydrophobicity, flexibility, and significantly the lost hydrogen bonds of the mutant compared to other compounds. Besides, we revealed changes in the free energy landscape (FEL) of WT-SOD1 and mutant states (unbound/bound) to differentiate aggregation. We deduced that the above-mentioned flavonoids can deviation the pathogenic behaviour of the D124 V mutant. Among them, Salvianolic acid A showed the greatest therapeutic potential against the D124 V mutant. Hence, Salvianolic acid A could serve as a drug candidate for the design of highly efficient inhibitors in reducing fatal and irreversible ALS.

Aβ1-42 stimulates an increase in autophagic activity through tunicamycin-induced endoplasmic reticulum stress in HTR-8/SVneo cells and late-onset pre-eclampsia.

Environmental changes can trigger endoplasmic reticulum (ER) stress and misfolded protein accumulation, potentially leading to pre-eclampsia (PE). Amyloid-β (Aβ) is a crucial misfolded protein that can overactivate autophagy. Our study assessed the expression of Aβ1-42 and autophagic activity in PE placental tissues and trophoblasts under ER stress. Placental tissues were surgically collected from normal pregnant women (NP) and pregnant women with late-onset PE (LOPE) delivering through cesarean section. The expression levels of Aβ1-42 were detected in both PE and NP placental tissues, as well as in tunicamycin (TM)-induced HTR-8/SVneo cells. Autophagy-related proteins, such as Beclin-1, the ratio of LC3-II to LC3-I, ATG5, and SQSTM1/p62 in the placental tissues and HTR-8/SVneo cells were measured by Western blot. The number and morphology of autophagosomes were observed using transmission electron microscopy (TEM). Potential targets associated with the unfolded protein response (UPR) in the placental tissues of NP and PE cases were screened using PCR Arrays. The misfolded protein was significantly upregulated in the PE group. In both PE placental tissues and TM-induced HTR-8/SVneo cells, not only was Aβ1-42 upregulated, but also Beclin-1, ATG5, and LC3BII/I were significantly increased, accompanied by an increase in autophagosome count, while SQSTM1/P62 was downregulated. A total of 17 differentially expressed genes (DEGs) associated with the UPR were identified, among which elevated calnexin (CANX) was validated in the placenta from both PE and TM-induced HTR-8/SVneo cells. Autophagy is significantly upregulated in PE cases due to ER stress-induced Aβ1-42 accumulation, likely mediated by autophagy-related proteins involved in the UPR.

Valproate Mediated Proteasome Dysfunctions Induce Apoptosis

AbstractSeveral studies suggest Valproate's (VPA) therapeutic use in treating seizures, epilepsy, and bipolar disorder. Valproate is a class I histone deacetylases (HDACs) inhibitor and an attractive chemotherapeutic agent for targeting cancer. Few reports suggest that Valproate can suppress cell growth and cell differentiation and is linked with anti‐tumor activity. However, Valproate‐associated anti‐tumoral function and intracellular signaling cascade‐mediated anti‐cellular proliferation activities still need to be better understood. This current study suggests that Valproate can elevate proteasomal dysfunctions, resulting in misfolded protein accumulation and abnormal mitochondrial functions that successively induce apoptosis. Present findings indicate that treatment of Valproate inhibits Proteasome activities and also aggravates accumulation of expanded polyglutamine proteins and other proteasomal substrates. Overall, the aggregation of aberrant proteins and mitochondrial dysfunctions are observed, such as cytochrome c release, and disturbed mitochondrial membrane potential. Treatment of Valproate induces apoptotic morphological changes and cell death. These observations suggest that Valproate can cause mitochondrial abnormalities associated with apoptosis. These findings can provide new possible insights and suggest molecular approaches for developing better and specific Proteasome inhibitors that can be better useful with other anti‐tumor drugs for treatment of cancer and other complex diseases.

A Proteomic Approach Identified TFEB as a Key Player in the Protective Action of Novel CB2R Bitopic Ligand FD22a against the Deleterious Effects Induced by β-Amyloid in Glial Cells.

Neurodegenerative diseases (NDDs) are progressive multifactorial disorders of the nervous system sharing common pathogenic features, including intracellular misfolded protein aggregation, mitochondrial deficit, and inflammation. Taking into consideration the multifaceted nature of NDDs, development of multitarget-directed ligands (MTDLs) has evolved as an attractive therapeutic strategy. Compounds that target the cannabinoid receptor type II (CB2R) are rapidly emerging as novel effective MTDLs against common NDDs, such as Alzheimer's disease (AD). We recently developed the first CB2R bitopic/dualsteric ligand, namely FD22a, which revealed the ability to induce neuroprotection with fewer side effects. To explore the potential of FD22a as a multitarget drug for the treatment of NDDs, we investigated here its ability to prevent the toxic effect of β-amyloid (Aβ25-35 peptide) on human cellular models of neurodegeneration, such as microglia (HMC3) and glioblastoma (U87-MG) cell lines. Our results displayed that FD22a efficiently prevented Aβ25-35 cytotoxic and proinflammatory effects in both cell lines and counteracted β-amyloid-induced depression of autophagy in U87-MG cells. Notably, a quantitative proteomic analysis of U87-MG cells revealed that FD22a was able to potently stimulate the autophagy-lysosomal pathway (ALP) by activating its master transcriptional regulator TFEB, ultimately increasing the potential of this novel CB2R bitopic/dualsteric ligand as a multitarget drug for the treatment of NDDs.

Misfolded protein deposits in Parkinson’s disease and Parkinson’s disease-related cognitive impairment, a [11C]PBB3 study

Parkinson’s disease (PD) is associated with aggregation of misfolded α-synuclein and other proteins, including tau. We designed a cross-sectional study to quantify the brain binding of [11C]PBB3 (a ligand known to bind to misfolded tau and possibly α-synuclein) as a proxy of misfolded protein aggregation in Parkinson’s disease (PD) subjects with and without cognitive impairment and healthy controls (HC). In this cross-sectional study, nineteen cognitively normal PD subjects (CN-PD), thirteen cognitively impaired PD subjects (CI-PD) and ten HC underwent [11C]PBB3 PET. A subset of the PD subjects also underwent PET imaging with [11C](+)DTBZ to assess dopaminergic denervation and [11C]PBR28 to assess neuroinflammation. Compared to HC, PD subjects showed higher [11C]PBB3 binding in the posterior putamen but not the substantia nigra. There was no relationship across subjects between [11C]PBB3 and [11C]PBR28 binding in nigrostriatal regions. [11C]PBB3 binding was increased in the anterior cingulate in CI-PD compared to CN-PD and HC, and there was an inverse correlation between cognitive scores and [11C]PBB3 binding in this region across all PD subjects. Our results support a primary role of abnormal protein deposition localized to the posterior putamen in PD. This suggests that striatal axonal terminals are preferentially involved in the pathophysiology of PD. Furthermore, our findings suggest that anterior cingulate pathology might represent a significant in vivo marker of cognitive impairment in PD, in agreement with previous neuropathological studies.

The role of labile iron on brain proteostasis; could it be an early event of neurodegenerative disease?

Iron deposits in the brain are a natural consequence of aging. Iron accumulation, especially in the form of labile iron, can trigger a cascade of adverse effects, eventually leading to neurodegeneration and cognitive decline. Aging also increases the dysfunction of cellular proteostasis. The question of whether iron alters proteostasis is now being pondered. Herein, we investigated the effect of ferric citrate, considered as labile iron, on various aspects of proteostasis of neuronal cell lines, and also established an animal model having a labile iron diet in order to evaluate proteostasis alteration in the brain along with behavioral effects. According to an in vitro study, labile iron was found to activate lysosome formation but inhibits lysosomal clearance function. Furthermore, the presence of labile iron can alter autophagic flux and can also induce the accumulation of protein aggregates. RNA-sequencing analysis further reveals the upregulation of various terms related to proteostasis along with neurodegenerative disease-related terms. According to an in vivo study, a labile iron-rich diet does not induce iron overload conditions and was not detrimental to the behavior of male Wistar rats. However, an iron-rich diet can promote iron accumulation in a region-dependent manner. By staining for autophagic markers and misfolding proteins in the cerebral cortex and hippocampus, an iron-rich diet was actually found to alter autophagy and induce an accumulation of misfolding proteins. These findings emphasize the importance of labile iron on brain cell proteostasis, which could be implicated in developing of neurological diseases.