Alzheimer and Parkinson’s diseases are neurodegenerative aging-related pathological conditions, mainly caused by the interplay of genetic and non-genetic factors and whose incidence rate is going to ...drastically increase given the growing life expectancy. To address these complex multifactorial traits, a systems biology strategy is needed to highlight genotype–phenotype correlations as well as overlapping gene signatures. Copy number variants (CNVs) are structural chromosomal imbalances that can have pathogenic nature causing or contributing to the disease onset or progression. Moreover, neurons affected by CNVs have been found to decline in number depending on age in healthy controls and may be selectively vulnerable to aging-related cell-death. In this review, we aim to update the reader on the role of these variations in the pathogenesis of Alzheimer and Parkinson diseases. To widen the comprehension of pathogenic mechanisms underlying them, we discuss variations detected from blood or brain specimens, as well as overlapped signatures between the two pathologies.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Based on transcriptional profiles of motor cortex samples, in a ...previous work, we were able to classify two subgroups of sporadic ALS (SALS) patients, named SALS1 and SALS2. A further meta‐analysis study has revealed sixteen drug targets commonly deregulated in SALS2 and superoxide dismutase 1 (SOD1) G93A mice. The identified candidate drug targets included pituitary adenylate cyclase‐activating polypeptide (PACAP), epidermal growth factor receptor (EGFR) and matrix metallopeptidase‐2 (MMP‐2). By using a motor neuron‐like hybrid cell line (NSC‐34) expressing human SOD1 G93A as an in vitro model of ALS, here we investigated the functional correlation among these three genes. Our results have shown that PACAP increases cell viability following serum deprivation. This effect is induced through EGFR transactivation mediated by protein kinase A stimulation. Furthermore, EGFR phosphorylation activates mitogen‐activated protein kinases/extracellular signal‐regulated kinases 1 and 2 survival signaling pathway and increases MMP‐2 expression, significantly reduced by serum starvation. These results suggest that a deeper characterization of mechanisms involved in PACAP/EGFR/MMP‐2 axis activation in G93A SOD1 mutated neurons may allow identifying new targets for ALS therapy.
Pituitary adenylate cyclase‐activating polypeptide (PACAP) increased cell viability of human superoxide dismutase 1 (SOD1) G93A cells following serum deprivation PACAP induced epidermal growth factor receptor (EGFR) transactivation mediated by protein kinase A stimulation EGFR phosphorylation activated mitogen‐activated protein kinases/extracellular signal‐regulated kinases 1 and 2 (MAPK/ERK1/2) survival signaling pathway.
The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new ...leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX).
Regenerative medicine is a branch of translational research that aims to reestablish irreparably damaged tissues and organs by stimulating the body’s own repair mechanisms
via
the implantation of ...stem cells differentiated into specialized cell types. A rich source of adult stem cells is located inside the tooth and is represented by human dental pulp stem cells, or hDPSCs. These cells are characterized by a high proliferative rate, have self-renewal and multi-lineage differentiation properties and are often used for tissue engineering and regenerative medicine. The present review will provide an overview of hDPSCs and related features with a special focus on their potential applications in regenerative medicine of the nervous system, such as, for example, after spinal cord injury. Recent advances in the identification and characterization of dental stem cells and in dental tissue engineering strategies suggest that bioengineering approaches may successfully be used to regenerate districts of the central nervous system, previously considered irreparable.
Molecular and clinical heterogeneity is increasingly recognized as a common characteristic of neurodegenerative diseases (NDs), such as Alzheimer’s disease, Parkinson’s disease and amyotrophic ...lateral sclerosis. This heterogeneity makes difficult the development of early diagnosis and effective treatment approaches, as well as the design and testing of new drugs. As such, the stratification of patients into meaningful disease subgroups, with clinical and biological relevance, may improve disease management and the development of effective treatments. To this end, omics technologies—such as genomics, transcriptomics, proteomics and metabolomics—are contributing to offer a more comprehensive view of molecular pathways underlying the development of NDs, helping to differentiate subtypes of patients based on their specific molecular signatures. In this article, we discuss how omics technologies and their integration have provided new insights into the molecular heterogeneity underlying the most prevalent NDs, aiding to define early diagnosis and progression markers as well as therapeutic targets that can translate into stratified treatment approaches, bringing us closer to the goal of personalized medicine in neurology.
More than 1 billion world's population actively smokes tobacco containing the bioactive component nicotine (NT). The biological role of this molecule is mediated through the activation of nicotinic ...cholinergic receptors, widely distributed in various human tissues including retinal pigmented epithelium. The long-term assumption of NT contributes to several diseases development such as diabetic retinopathy. The major complication of this pathology is the diabetic macular edema (DME), characterized by macular area thinning and blood-retinal barrier (BRB) breakdown. Retinal hyperglycemic/hypoxic microenvironment represents one of the main factors favoring DME progression by eliciting the hypoxia-inducible factors (HIFs) expression. The latter induce new vessels formation by stimulating cellular secretion of vascular endothelial growth factor (VEGF).
The etiology of DME is multifactorial, but little is known about the risk factors linked to cigarette smoking, in particular to nicotine's contribution.
In the present study, we have investigated the NT role in a model, in vitro, of DME, by evaluating its effect on outer BRB permeability and HIFs/VEGF expression following exposure to hyperglycemic/hypoxic insult.
Our results have demonstrated that this compound alters outer BRB integrity exposed to high glucose and low oxygen pressure microenvironment by upregulating HIF-1α/HIF-2α, VEGF expression and ERK1/2 phosphorylation.
These data have suggested that NT may play a negative role in active smokers affected by DME.
•Nicotine (NT) is involved in the development of diabetic macular edema.•NT alters outer BRB integrity exposed to hyperglycemic/hypoxic insult.•NT potentiates the hypoxic vicious cycle responsible of DME progression.•NT induces up-regulation of HIF-1α/HIF-2α, VEGF/VEGFRs and ERK1/2 pathway.
Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem genetic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded ...substrates inside the lysosome. Although the cellular pathogenesis of LSDs is complex and still not fully understood, the approval of disease-specific therapies and the rapid emergence of novel diagnostic methods led to the implementation of extensive national newborn screening (NBS) programs in several countries. In the near future, this will help the development of standardized workflows aimed to more timely diagnose these conditions. Hereby, we report an overview of LSD diagnostic process and treatment strategies, provide an update on the worldwide NBS programs, and discuss the opportunities and challenges arising from genomics applications in screening, diagnosis, and research.
With over 60 different disorders and a combined incidence occurring in 1:5000-7000 live births, lysosomal storage diseases (LSDs) represent a major public health problem and constitute an enormous ...burden for affected individuals and their families. Several reasons make the diagnosis of LSDs an arduous task for clinicians, including the phenotype and penetrance variability, the shared signs and symptoms, and the uncertainties related to biochemical enzymatic assay results. Developing a powerful diagnostic tool based on next generation sequencing (NGS) technology may help reduce the delayed diagnostic process for these families, leading to better outcomes for current therapies and providing the basis for more appropriate genetic counseling. Herein, we employed a targeted NGS-based panel to scan the coding regions of 65 LSD-causative genes. A reference group sample (
= 26) with previously known genetic mutations was used to test and validate the entire workflow. Our approach demonstrated elevated analytical accuracy, sensitivity, and specificity. We believe the adoption of comprehensive targeted sequencing strategies into a routine diagnostic route may accelerate both the identification and management of LSDs with overlapping clinical profiles, producing a significant reduction in delayed diagnostic response with beneficial results in the treatment outcome.
Gliomas account for the majority of primary brain tumors. Glioblastoma is the most common and malignant type. Based on their extreme molecular heterogeneity, molecular markers can be used to classify ...gliomas and stratify patients into diagnostic, prognostic, and therapeutic clusters. In this work, we developed and validated a targeted next-generation sequencing (NGS) approach to analyze variants or chromosomal aberrations correlated with tumorigenesis and response to treatment in gliomas. Our targeted NGS analysis covered 13 glioma-related genes (ACVR1, ATRX, BRAF, CDKN2A, EGFR, H3F3A, HIST1H3B, HIST1H3C, IDH1, IDH2, P53, PDGFRA, PTEN), a 125 bp region of the TERT promoter, and 54 single nucleotide polymorphisms (SNPs) along chromosomes 1 and 19 for reliable assessment of their copy number alterations (CNAs). Our targeted NGS approach provided a portrait of gliomas’ molecular heterogeneity with high accuracy, specificity, and sensitivity in a single workflow, enabling the detection of variants associated with unfavorable outcomes, disease progression, and drug resistance. These preliminary results support its use in routine diagnostic neuropathology.
Lysosomal storage diseases (LSDs) are a heterogeneous group of approximately 70 monogenic metabolic disorders whose diagnosis represents an arduous challenge for clinicians due to their variability ...in phenotype penetrance, clinical manifestations, and high allelic heterogeneity. In recent years, the approval of disease-specific therapies and the rapid emergence of novel rapid diagnostic methods has opened, for a set of selected LSDs, the possibility for inclusion in extensive national newborn screening (NBS) programs. Herein, we evaluated the clinical utility and diagnostic validity of a targeted next-generation sequencing (tNGS) panel (called NBS_LSDs), designed ad hoc to scan the coding regions of six genes (GBA, GAA, SMPD1, IDUA1, GLA, GALC) relevant for a group of LSDs candidate for inclusion in national NBS programs (MPSI, Pompe, Fabry, Krabbe, Niemann Pick A-B and Gaucher diseases). A standard group of 15 samples with previously known genetic mutations was used to test and validate the entire flowchart. Analytical accuracy, sensitivity, and specificity, as well as turnaround time and costs, were assessed. Results showed that the Ion AmpliSeq and Ion Chef System-based high-throughput NBS_LSDs tNGS panel is a fast, accurate, and cost-effective process. The introduction of this technology into routine NBS procedures as a second-tier test along with primary biochemical assays will allow facilitating the identification and management of selected LSDs and reducing diagnostic delay.
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