Exploring the role of high-mobility group box 1 (HMGB1) protein in the pathogenesis of Huntington’s disease

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by an increased and unstable CAG DNA expansion in the Huntingtin (HTT) gene, resulting in an elongated polyglutamine tract in huntingtin protein. Despite its monogenic cause, HD pathogenesis remains elusive and without any approved disease-modifying therapy as yet. A growing body of evidence highlights the emerging role of high-mobility group box 1 (HMGB1) protein in HD pathology. HMGB1, being a nuclear protein, is primarily implicated in DNA repair, but it can also translocate to the cytoplasm and participate into numerous cellular functions. Cytoplasmic HMGB1 was shown to directly interact with huntingtin under oxidative stress conditions and induce its nuclear translocation, a key process in the HD pathogenic cascade. Nuclear HMGB1 acting as a co-factor of ataxia telangiectasia mutated and base excision repair (BER) complexes can exert dual roles in CAG repeat instability and affect the final DNA repair outcome. HMGB1 can inhibit mutant huntingtin aggregation, protecting against polyglutamine-induced neurotoxicity and acting as a chaperon-like molecule, possibly via autophagy regulation. In addition, HMGB1 being a RAGE and TLR-2, TLR-3, and TLR-4 ligand may further contribute to HD pathogenesis by triggering neuroinflammation and apoptosis. Furthermore, HMGB1 participates at the unfolded protein response (UPR) system and can induce protein degradation and apoptosis associated with HD. In this review, we discuss the multiple role of HMGB1 in HD pathology, providing mechanistic insights that could direct future studies towards the development of targeted therapeutic approaches. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Critical role of HOX transcript antisense intergenic RNA (HOTAIR) in gliomas

Despite extensive research, gliomas are associated with high morbidity and mortality, mainly attributed to the rapid growth rate, excessive invasiveness, and molecular heterogeneity, as well as regenerative potential of cancer stem cells. Therefore, elucidation of the underlying molecular mechanisms and the identification of potential molecular diagnostic and prognostic biomarkers are of paramount importance. HOX transcript antisense intergenic RNA (HOTAIR) is a well-studied long noncoding RNA, playing an emerging role in tumorigenesis of several human cancers. A growing amount of preclinical and clinical evidence highlights the pro-oncogenic role of HOTAIR in gliomas, mainly attributed to the enhancement of proliferation and migration, as well as inhibition of apoptosis. In vitro and in vivo studies demonstrate that HOTAIR modulates the activity of specific transcription factors, such as MXI1, E2F1, ATF5, and ASCL1, and regulates the expression of cell cycle–associated genes along with related signaling pathways, like the Wnt/β-catenin axis. Moreover, it can interact with specific miRNAs, including miR-326, miR-141, miR-148b-3p, miR-15b, and miR-126-5p. Of importance, HOTAIR has been demonstrated to enhance angiogenesis and affect the permeability of the blood–tumor barrier, thus modulating the efficacy of chemotherapeutic agents. Herein, we provide evidence on the functional role of HOTAIR in gliomas and discuss the benefits of its targeting as a novel approach toward glioma treatment. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Emerging Pathogenic and Prognostic Significance of Paired Box 3 (PAX3) Protein in Adult Gliomas

Gliomas present the most common type of brain tumors in adults, characterized by high morbidity and mortality. In search of potential molecular targets, members of paired box (PAX) family have been found expressed in neural crest cells, regulating their proliferation, apoptosis, migration and differentiation. Recently, PAX3 overexpression has been implicated in glioma tumorigenesis by enhancing proliferation, increasing invasiveness and inducing resistance to apoptosis of glioma cells, while maintaining brain glioma stem cells (BGSCs) stemness. Although the oncogenic potential of PAX3 in gliomas is still under investigation, experimental evidence suggests that PAX3 function is mainly mediated through the canonical and non-canonical Wnt signaling pathway as well as through its interaction with GFAP and p53 proteins. In addition, PAX3 may contribute to the chemoresistance of glioma cells and modulates the effectiveness of novel experimental therapies. Further evidence indicates that PAX3 may represent a novel diagnostic and prognostic biomarker for gliomas, facilitating personalized treatment. This review addresses the emerging role of PAX3 in glioma diagnosis, prognosis and treatment, aiming to shed more light on the underlying molecular mechanisms that could lead to more effective treatment approaches. © 2019 The Author

Unraveling the Role of Receptor for Advanced Glycation End Products (RAGE) and Its Ligands in Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune T cell-dependent B cell-mediated disorder of the neuromuscular junction (NMJ) characterized by fluctuating skeletal muscle weakness, most commonly attributed to pathogenic autoantibodies against postsynaptic nicotinic acetylcholine receptors (AChRs). Although MG pathogenesis is well-documented, there are no objective biomarkers that could effectively correlate with disease severity or MG clinical subtypes, and current treatment approaches are often ineffective. The receptor for advanced glycation end products (RAGE) is a multiligand cell-bound receptor highly implicated in proinflammatory responses and autoimmunity. Preclinical evidence demonstrates that RAGE and its ligand S100B are upregulated in rat models of experimental autoimmune myasthenia gravis (EAMG). S100B-mediated RAGE activation has been shown to exacerbate EAMG, by enhancing T cell proinflammatory responses, aggravating T helper (Th) subset imbalance, increasing AChR-specific T cell proliferative capacity, and promoting the production of antibodies against AChRs from the spleen. Soluble sRAGE and esRAGE, acting as decoys of RAGE ligands, are found to be significantly reduced in MG patients. Moreover, MG has been associated with increased serum levels of S100A12, S100B and HMGB1. Several studies have shown that the presence of thymic abnormalities, the onset age of MG, and the duration of the disease may affect the levels of these proteins in MG patients. Herein, we discuss the emerging role of RAGE and its ligands in MG immunopathogenesis, their clinical significance as promising biomarkers, as well as the potential therapeutic implications of targeting RAGE signaling in MG treatment. Copyright © 2020 American Chemical Society

miR-124 and Parkinson's disease: A biomarker with therapeutic potential

Parkinson's disease (PD) is a multifactorial disorder, attributed to a complex interplay between genetic and epigenetic factors. Although the exact etiology of the disease remains elusive, dysregulation of signaling pathways implicated in cell survival, apoptosis, protein aggregation, mitochondrial dysfunction, autophagy, oxidative damage and neuroinflammation, contributes to its pathogenesis. MicroRNAs (miRs) are endogenous short non-coding RNA molecules that negatively regulate gene expression at a post-transcriptional level. MiR-124 is one of the most abundantly expressed miRs in the brain that participates in neurogenesis, synapse morphology, neurotransmission, inflammation, autophagy and mitochondrial function. Accumulating pre-clinical evidence shows that miR-124 may act through calpain 1/p25/cyclin-dependent kinases 5 (CDK5), nuclear factor-kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), Bcl-2-interacting mediator of cell death (Bim), 5′ adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK)-mediated pathways to regulate cell survival, apoptosis, autophagy, mitochondrial dysfunction, oxidative damage and neuroinflammation in PD. Moreover, clinical evidence indicates that reduced plasma miR-124 levels may serve as a potential diagnostic biomarker in PD. This review provides an update of the pathogenic implication of miR-124 activity in PD and discusses its targeting potential for the development of future therapeutic strategies. © 2019 Elsevier Lt

Emerging role of S100B protein implication in Parkinson’s disease pathogenesis

The exact etiology of Parkinson’s disease (PD) remains obscure, lacking effective diagnostic and prognostic biomarkers. In search of novel molecular factors that may contribute to PD pathogenesis, emerging evidence highlights the multifunctional role of the calcium-binding protein S100B that is widely expressed in the brain and predominantly in astrocytes. Preclinical evidence points towards the possible time-specific contributing role of S100B in the pathogenesis of neurodegenerative disorders including PD, mainly by regulating neuroinflammation and dopamine metabolism. Although existing clinical evidence presents some contradictions, estimation of S100B in the serum and cerebrospinal fluid seems to hold a great promise as a potential PD biomarker, particularly regarding the severity of motor and non-motor PD symptoms. Furthermore, given the recent development of S100B inhibitors that are able to cross the blood brain barrier, novel opportunities are arising in the research field of PD therapeutics. In this review, we provide an update on recent advances in the implication of S100B protein in the pathogenesis of PD and discuss relevant studies investigating the biomarker potential of S100B in PD, aiming to shed more light on clinical targeting approaches related to this incurable disorder. © 2020, Springer Nature Switzerland AG

Role of Liver Growth Factor (LGF) in Parkinson’s Disease: Molecular Insights and Therapeutic Opportunities

Parkinson’s disease is the most common neurodegenerative movement disorder with unclear etiology and only symptomatic treatment to date. Toward the development of novel disease-modifying agents, neurotrophic factors represent a reasonable and promising therapeutic approach. However, despite the robust preclinical evidence, clinical trials using glial-derived neurotrophic factor (GDNF) and neurturin have been unsuccessful. In this direction, the therapeutic potential of other trophic factors in PD and the elucidation of the underlying molecular mechanisms are of paramount importance. The liver growth factor (LGF) is an albumin–bilirubin complex acting as a hepatic mitogen, which also exerts regenerative effects on several extrahepatic tissues including the brain. Accumulating evidence suggests that intracerebral and peripheral administration of LGF can enhance the outgrowth of nigrostriatal dopaminergic axonal terminals; promote the survival, migration, and differentiation of neuronal stem cells; and partially protect against dopaminergic neuronal loss in the substantia nigra of PD animal models. In most studies, these effects are accompanied by improved motor behavior of the animals. Potential underlying mechanisms involve transient microglial activation, TNF-α upregulation, and activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) and of the transcription factor cyclic AMP response-element binding protein (CREB), along with anti-inflammatory and antioxidant pathways. Herein, we summarize recent preclinical evidence on the potential role of LGF in PD pathogenesis, aiming to shed more light on the underlying molecular mechanisms and reveal novel therapeutic opportunities for this debilitating disease. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature

Arylsulfatase a (Asa) in parkinson’s disease: From pathogenesis to biomarker potential

Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is a clinically heterogeneous disorder, with obscure etiology and no disease-modifying therapy to date. Currently, there is no available biomarker for PD endophenotypes or disease progression. Accumulating evidence suggests that mutations in genes related to lysosomal function or lysosomal storage disorders may affect the risk of PD development, such as GBA1 gene mutations. In this context, recent studies have revealed the emerging role of arylsulfatase A (ASA), a lysosomal hydrolase encoded by the ARSA gene causing metachromatic leukodystrophy (MLD) in PD pathogenesis. In particular, altered ASA levels have been detected during disease progression, and reduced enzymatic activity of ASA has been associated with an atypical PD clinical phenotype, including early cognitive impairment and essential-like tremor. Clinical evidence further reveals that specific ARSA gene variants may act as genetic modifiers in PD. Recent in vitro and in vivo studies indicate that ASA may function as a molecular chaperone interacting with α-synuclein (SNCA) in the cytoplasm, preventing its aggregation, secretion and cell-to-cell propagation. In this review, we summarize the results of recent preclinical and clinical studies on the role of ASA in PD, aiming to shed more light on the potential implication of ASA in PD pathogenesis and highlight its biomarker potential. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Impact of the apelin/APJ axis in the pathogenesis of Parkinson’s disease with therapeutic potential

The pathogenesis of Parkinson's disease (PD) remains elusive. There is still no available disease-modifying strategy against PD, whose management is mainly symptomatic. A growing amount of preclinical evidence shows that a complex interplay between autophagy dysregulation, mitochondrial impairment, endoplasmic reticulum stress, oxidative stress, and excessive neuroinflammation underlies PD pathogenesis. Identifying key molecules linking these pathological cellular processes may substantially aid in our deeper understanding of PD pathophysiology and the development of novel effective therapeutic approaches. Emerging preclinical evidence indicates that apelin, an endogenous neuropeptide acting as a ligand of the orphan G protein-coupled receptor APJ, may play a key neuroprotective role in PD pathogenesis, via inhibition of apoptosis and dopaminergic neuronal loss, autophagy enhancement, antioxidant effects, endoplasmic reticulum stress suppression, as well as prevention of synaptic dysregulation in the striatum, excessive neuroinflammation, and glutamate-induced excitotoxicity. Underlying signaling pathways involve phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin, extracellular signal-regulated kinase 1/2, and inositol requiring kinase 1α/XBP1/C/EBP homologous protein. Herein, we discuss the role of apelin/APJ axis and associated molecular mechanisms on the pathogenesis of PD in vitro and in vivo and provide evidence for its challenging therapeutic potential. © 2021 Wiley Periodicals, Inc

Fractalkine (CX3CL1) signaling and neuroinflammation in Parkinson's disease: Potential clinical and therapeutic implications

Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD) with the dysregulation of microglial activity being tightly linked to dopaminergic degeneration. Fractalkine (CX3CL1), a chemokine mainly expressed by neurons, can modulate microglial activity through binding to its sole G-protein-coupled receptor (CX3CR1), expressed by microglia. Fractalkine/CX3CR1 signaling is one of the most important mediators of the communication between neurons and microglia, and its emerging role in neurodegenerative disorders including PD has been increasingly recognized. Pre-clinical evidence has revealed that fractalkine signaling axis exerts dual effects on PD-related inflammation and degeneration, which greatly depend on the isoform type (soluble or membrane-bound), animal model (mice or rats, toxin- or proteinopathy-induced), route of toxin administration, time course and specific brain region (striatum, substantia nigra). Furthermore, although existing clinical evidence is scant, it has been indicated that fractalkine may be possibly associated with PD progression, paving the way for future studies investigating its biomarker potential. In this review, we discuss recent evidence on the role of fractalkine/CX3CR1 signaling axis in PD pathogenesis, aiming to shed more light on the molecular mechanisms underlying the neuroinflammation commonly associated with the disease, as well as potential clinical and therapeutic implications. © 2020 Elsevier Lt