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Molecular Neurobiology of Neurodegenerative Diseases

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 11498

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Special Issue Editors

Dr. Ignazio Stefano Piras

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Guest Editor

Translational Genomics Research Institute, Phoenix, AZ, USA
Interests: human genetics; genetic analysis; molecular genetics; gene expression; epigenetics; DNA; next generation sequencing; genomics; genotyping; brain

Dr. Valerio Napolioni

E-Mail Website
Guest Editor

School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
Interests: genomic epidemiology; neurogenetics; molecular psychiatry; complex traits; next-generation sequencing; neurodegeneration; behavioral traits; autism; dementia

Special Issue Information

Dear Colleagues,

The unprecedented development of high-throughput “omics” technologies that has occurred in the last 15 years is allowing the dissection of complex biological phenomena underlying the physiological/homeostatic derangements occurring in most of common diseases. Large-scale omics studies in neurodegenerative diseases, both in human and animal models, have allowed the discovery of novel risk factors and the molecular neurobiological pathways involved in their pathogenesis.

Despite the large-scale studies conducted so far, a deeper knowledge is further needed to help in translating the recently discovered molecular mechanisms into clinical settings, from the development of early diagnosis biomarkers to the development of new pharmacological treatments.

We are inviting the submission of original articles to this Special Issue of the Journal of Personalized Medicine that report new findings in the molecular neurobiological bases of neurodegenerative diseases, coming from omics-based approaches (e.g., from genomics to proteomics) or from functional studies (e.g., in vitro and in vivo studies).

Dr. Ignazio Stefano Piras
Prof. Valerio Napolioni
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular biology
genomics
proteomics
transcriptomics
epigenomics
animal models
cell cultures
rare diseases
neurodegeneration
molecular pathways

Published Papers (4 papers)

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Research

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18 pages, 2831 KiB

Open AccessArticle

Olfactory Bulb Proteomics Reveals Widespread Proteostatic Disturbances in Mixed Dementia and Guides for Potential Serum Biomarkers to Discriminate Alzheimer Disease and Mixed Dementia Phenotypes

by Mercedes Lachén-Montes, Ignacio Íñigo-Marco, Paz Cartas-Cejudo, Joaquín Fernández-Irigoyen and Enrique Santamaría

J. Pers. Med. 2021, 11(6), 503; https://doi.org/10.3390/jpm11060503 - 03 Jun 2021

Cited by 4 | Viewed by 2574

Abstract

The most common form of mixed dementia (MixD) is constituted by abnormal protein deposits associated with Alzheimer’s disease (AD) that coexist with vascular disease. Although olfactory dysfunction is considered a clinical sign of AD-related dementias, little is known about the impact of this sensorial impairment in MixD at the molecular level. To address this gap in knowledge, we assessed olfactory bulb (OB) proteome-wide expression in MixD subjects (n = 6) respect to neurologically intact controls (n = 7). Around 9% of the quantified proteins were differentially expressed, pinpointing aberrant proteostasis involved in synaptic transmission, nucleoside monophosphate and carbohydrate metabolism, and neuron projection regeneration. In addition, network-driven proteomics revealed a modulation in cell-survival related pathways such as ERK, AKT, and the PDK1-PKC axis. Part of the differential OB protein set was not specific of MixD, also being deregulated across different tauopathies, synucleinopathies, and tardopathies. However, the comparative functional analysis of OB proteome data between MixD and pure AD pathologies deciphered commonalities and differences between both related phenotypes. Finally, olfactory proteomics allowed to propose serum Prolow-density lipoprotein receptor-related protein 1 (LRP1) as a candidate marker to differentiate AD from MixD phenotypes. Full article

(This article belongs to the Special Issue Molecular Neurobiology of Neurodegenerative Diseases)

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15 pages, 3705 KiB

Open AccessArticle

A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study

by Syuan-Yu Hong, Jiann-Jou Yang, Shuan-Yow Li and Inn-Chi Lee

J. Pers. Med. 2020, 10(4), 281; https://doi.org/10.3390/jpm10040281 - 15 Dec 2020

Cited by 16 | Viewed by 3116

Abstract

Background: Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients. Methods: Patients with refractory seizures using ≥2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclusion criteria, were enrolled, and underwent WES. Results: Genetic diagnoses were confirmed in 24 patients. In the seizure group, KCNQ2, SCN1A, TBCID 24, GRIN1, IRF2BPL, MECP2, OSGEP, PACS1, PIGA, PPP1CB, SMARCA4, SUOX, SZT2, UBE3A, 16p13.11 microdeletion, [4p16.3p16.1(68,345–7,739,782)X1, 17q25.1q25.3(73,608,322–81,041,938)X3], and LAMA2 were identified. In the nonseizure group, SCN2A, SPTBN2, DMD, and FBN1 were identified. Ten novel mutations were identified. The recurrent genes included SCN1A, KCNQ2, and TBCID24. Male pediatric patients had a significantly higher (57% vs. 29%; p < 0.05, odds ratio = 3.18) yield than their female counterparts. Seventeen genes were identified from the seizure groups, of which 82% were rare genetic etiologies for childhood seizure and did not appear recurrently in the case series. Conclusions: Wide genetic variation was identified for severe childhood seizures by WES. WES had a high yield, particularly in male infantile patients. Full article

(This article belongs to the Special Issue Molecular Neurobiology of Neurodegenerative Diseases)

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18 pages, 1310 KiB

Open AccessArticle

Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family

by Giovanna Morello, Giulia Gentile, Rossella Spataro, Antonio Gianmaria Spampinato, Maria Guarnaccia, Salvatore Salomone, Vincenzo La Bella, Francesca Luisa Conforti and Sebastiano Cavallaro

J. Pers. Med. 2020, 10(4), 262; https://doi.org/10.3390/jpm10040262 - 02 Dec 2020

Cited by 3 | Viewed by 2215

Abstract

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes. Full article

(This article belongs to the Special Issue Molecular Neurobiology of Neurodegenerative Diseases)

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Review

Jump to: Research

17 pages, 494 KiB

Open AccessReview

Genetic Counselling Improves the Molecular Characterisation of Dementing Disorders

by Stefania Zampatti, Michele Ragazzo, Cristina Peconi, Serena Luciano, Stefano Gambardella, Valerio Caputo, Claudia Strafella, Raffaella Cascella, Carlo Caltagirone and Emiliano Giardina

J. Pers. Med. 2021, 11(6), 474; https://doi.org/10.3390/jpm11060474 - 26 May 2021

Cited by 2 | Viewed by 2736

Abstract

Dementing disorders are a complex group of neurodegenerative diseases characterised by different, but often overlapping, pathological pathways. Genetics have been largely associated with the development or the risk to develop dementing diseases. Recent advances in molecular technologies permit analyzing of several genes in a small time, but the interpretation analysis is complicated by several factors: the clinical complexity of neurodegenerative disorders, the frequency of co-morbidities, and the high phenotypic heterogeneity of genetic diseases. Genetic counselling supports the diagnostic path, providing an accurate familial and phenotypic characterisation of patients. In this review, we summarise neurodegenerative dementing disorders and their genetic determinants. Genetic variants and associated phenotypes will be divided into high and low impact, in order to reflect the pathologic continuum between multifactorial and mendelian genetic factors. Moreover, we report a molecular characterisation of genes associated with neurodegenerative disorders with cognitive impairment. In particular, the high frequency of rare coding genetic variants in dementing genes strongly supports the role of geneticists in both, clinical phenotype characterisation and interpretation of genotypic data. The smart application of exome analysis to dementia patients, with a pre-analytical selection on familial, clinical, and instrumental features, improves the diagnostic yield of genetic test, reduces time for diagnosis, and allows a rapid and personalised management of disease. Full article

(This article belongs to the Special Issue Molecular Neurobiology of Neurodegenerative Diseases)

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