Valentina La Cognata

Institute for Biomedical Research and Innovation

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Sebastiano Cavallaro

National Research Council

Velia D’Agata

University of Catania

Giovanna Morello

Institute for Biomedical Research and Innovation

Maria Guarnaccia

National Research Council

Agata Grazia D’Amico

University of Catania

Grazia Maugeri

University of Catania

Rosario Iemmolo

Institute for Biomedical Research and Innovation

Salvatore Saccone

University of Catania

Gabriele Bonaventura

National Research Council

Concetta Federico

University of Catania

Cooperative Institutions

University of Catania

National Research Council

National Academies of Sciences, Engineering, and Medicine

Institute of Neurological Sciences

Institute for Biomedical Research and Innovation

Azienda Ospedaliero-Universitaria Policlinico - Vittorio Emanuele

Policlinico Universitario di Catania

Institute of Cell Biology and Neurobiology

Istituti di Ricovero e Cura a Carattere Scientifico

University of Palermo

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A Targeted Next-Generation Sequencing Panel to Genotype Gliomas

Life (2022)

Maria Guarnaccia Laura Guarnaccia Valentina La Cognata Stefania Elena Navone Rolando Campanella

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.

10.3390/life12070956

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Citations (4)

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

InTech eBooks (2016)

Valentina La Cognata Velia D’Agata Francesca Cavalcanti Sebastiano Cavallaro

Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

Mendelian inheritance

Structural Variation

Identification

Molecular Genetics

10.5772/62881

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Citations (3)

Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approach

Human Genetics (2016)

Valentina La Cognata Giovanna Morello Velia D’Agata Sebastiano Cavallaro

Mendelian inheritance

Human genetics

Molecular Genetics

Indel

Genome-wide Association Study

10.1007/s00439-016-1749-4

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Citations (58)

A Diagnostic Gene-Expression Signature in Fibroblasts of Amyotrophic Lateral Sclerosis

Cells (2023)

Giovanna Morello Valentina La Cognata Maria Guarnaccia Vincenzo La Bella F. L. Conforti

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease with limited treatment options. Diagnosis can be difficult due to the heterogeneity and non-specific nature of the initial symptoms, resulting in delays that compromise prompt access to effective therapeutic strategies. Transcriptome profiling of patient-derived peripheral cells represents a valuable benchmark in overcoming such challenges, providing the opportunity to identify molecular diagnostic signatures. In this study, we characterized transcriptome changes in skin fibroblasts of sporadic ALS patients (sALS) and controls and evaluated their utility as a molecular classifier for ALS diagnosis. Our analysis identified 277 differentially expressed transcripts predominantly involved in transcriptional regulation, synaptic transmission, and the inflammatory response. A support vector machine classifier based on this 277-gene signature was developed to discriminate patients with sALS from controls, showing significant predictive power in both the discovery dataset and in six independent publicly available gene expression datasets obtained from different sALS tissue/cell samples. Taken together, our findings support the utility of transcriptional signatures in peripheral cells as valuable biomarkers for the diagnosis of ALS.

Gene signature

10.3390/cells12141884

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Neuroprotective effect of the PACAP-ADNP axis on SOD1G93A mutant motor neuron death induced by trophic factors deprivation

Neuropeptides (2023)

Benedetta Magrì Agata Grazia D’Amico Grazia Maugeri Giovanna Morello Valentina La Cognata

10.1016/j.npep.2023.102386

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Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases

International Journal of Molecular Sciences (2021)

Valentina La Cognata Giovanna Morello Sebastiano Cavallaro

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.

Omics

Personalized Medicine

10.3390/ijms22094820

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Citations (28)

Alternative Splicing Generates Different Parkin Protein Isoforms: Evidences in Human, Rat, and Mouse Brain

BioMed Research International (2014)

Soraya Scuderi Valentina La Cognata Filippo Drago Sebastiano Cavallaro Velia D’Agata

Parkinson protein 2, E3 ubiquitin protein ligase (PARK2) gene mutations are the most frequent causes of autosomal recessive early onset Parkinson's disease and juvenile Parkinson disease. Parkin deficiency has also been linked to other human pathologies, for example, sporadic Parkinson disease, Alzheimer disease, autism, and cancer. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification. To date several PARK2 splice variants have been identified; however, the expression and distribution of parkin isoforms have not been deeply investigated yet. Here, the currently known PARK2 gene transcripts and relative predicted encoded proteins in human, rat, and mouse are reviewed. By analyzing the literature, we highlight the existing data showing the presence of multiple parkin isoforms in the brain. Their expression emerges from conflicting results regarding the electrophoretic mobility of the protein, but it is also assumed from discrepant observations on the cellular and tissue distribution of parkin. Although the characterization of each predicted isoforms is complex, since they often diverge only for few amino acids, analysis of their expression patterns in the brain might account for the different pathogenetic effects linked to PARK2 gene mutations.

10.1155/2014/690796

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Citations (40)

Table of Contents, Editor's Choice, Features

Journal of Cellular Biochemistry (2017)

Takato Hara Eiko Yoshida Yasuyuki Fujiwara Sung Woo Kim Jung Choi

Table (database)

Table of contents

10.1002/jcb.26119

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Detection of Single-Nucleotide and Copy Number Defects Underlying Hyperphenylalaninemia by Next-Generation Sequencing

Biomedicines (2023)

Elisabetta A. Tendi Giovanna Morello Maria Guarnaccia Valentina La Cognata Salvatore Petralia

Hyperphenylalaninemia (HPA) is the most common inherited amino acid metabolism disorder characterized by serious clinical manifestations, including irreversible brain damage, intellectual deficiency and epilepsy. Due to its extensive genic and allelic heterogeneity, next-generation sequencing (NGS) technology may help to identify the molecular basis of this genetic disease. Herein, we describe the development and validation of a targeted NGS (tNGS) approach for the simultaneous detection of single-nucleotide changes and copy number variations (CNVs) in genes associated with HPA (PAH, GCH1, PTS, QDPR, PCBD1, DNAJC12) or useful for its differential diagnosis (SPR). Our tNGS approach offers the possibility to detail, with a high accuracy and in a single workflow, the combined effect of a broader spectrum of genomic variants in a comprehensive view, providing a significant step forward in the development of optimized patient care and management.

Hyperphenylalaninemia

10.3390/biomedicines11071899

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CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A

Cells (2023)

Valentina La Cognata Agata Grazia D’Amico Grazia Maugeri Giovanna Morello Maria Guarnaccia

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy.

CXC chemokine receptors

10.3390/cells12141813

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Citations (6)