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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 30638

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Dr. Francesco Bruno

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Guest Editor

Regional Neurogenetic Center (CRN), Department of Primary Care, ASP Catanzaro, 88046 Lamezia Terme, Italy
Interests: neurological diseases; biomarkers; translational research; precision medicine; diagnosis; prognosis

Special Issue Information

Dear Colleagues,

Neurological diseases remain a major cause of disability and mortality and exert a serious social and financial burden. However, our understanding of the pathogenesis of neurological diseases at the molecular level is expanding day by day. Due to technological developments and new holistic approaches to translational research, an ever-increasing number of biomarkers at genomic, transcriptomic, epigenomic and proteomic levels are identified. These molecular biomarkers could allow to facilitate diagnosis, predict prognosis and guide treatment choices of patients with neurological diseases.

This special Issue in International Journal of Molecular Sciences on “Molecular Biomarkers in Neurological Diseases” will provide a monographic portrait of the current state of knowledge of molecular biomarkers for the diagnosis, prognosis, and neurological patients. Are especially welcome original research studies, review articles (either systematic or discursive), and short communications of preliminary, but significant, experimental results.

Dr. Francesco Bruno
Guest Editor

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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.

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Keywords

neurological diseases
biomarkers
translational research
precision medicine
diagnosis
prognosis

Published Papers (11 papers)

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Research

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12 pages, 621 KiB

Open AccessArticle

Upregulation of APAF1 and CSF1R in Peripheral Blood Mononuclear Cells of Parkinson’s Disease

by Kuo-Hsuan Chang, Chia-Hsin Liu, Yi-Ru Wang, Yen-Shi Lo, Chun-Wei Chang, Hsiu-Chuan Wu and Chiung-Mei Chen

Int. J. Mol. Sci. 2023, 24(8), 7095; https://doi.org/10.3390/ijms24087095 - 12 Apr 2023

Viewed by 1436

Abstract

Increased oxidative stress and neuroinflammation play a crucial role in the pathogenesis of Parkinson’s disease (PD). In this study, the expression levels of 52 genes related to oxidative stress and inflammation were measured in peripheral blood mononuclear cells of the discovery cohort including 48 PD patients and 25 healthy controls. Four genes, including ALDH1A, APAF1, CR1, and CSF1R, were found to be upregulated in PD patients. The expression patterns of these genes were validated in a second cohort of 101 PD patients and 61 healthy controls. The results confirmed the upregulation of APAF1 (PD: 0.34 ± 0.18, control: 0.26 ± 0.11, p < 0.001) and CSF1R (PD: 0.38 ± 0.12, control: 0.33 ± 0.10, p = 0.005) in PD patients. The expression level of APAF1 was correlated with the scores of the Unified Parkinson’s Disease Rating Scale (UPDRS, r = 0.235, p = 0.018) and 39-item PD questionnaire (PDQ-39, r = 0.250, p = 0.012). The expression level of CSF1R was negatively correlated with the scores of the mini-mental status examination (MMSE, r = −0.200, p = 0.047) and Montréal Cognitive Assessment (MoCA, r = −0.226, p = 0.023). These results highly suggest that oxidative stress biomarkers in peripheral blood may be useful in monitoring the progression of motor disabilities and cognitive decline in PD patients. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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16 pages, 3842 KiB

Open AccessArticle

Saliva and Saliva Extracellular Vesicles for Biomarker Candidate Identification—Assay Development and Pilot Study in Amyotrophic Lateral Sclerosis

by Sebastian Sjoqvist and Kentaro Otake

Int. J. Mol. Sci. 2023, 24(6), 5237; https://doi.org/10.3390/ijms24065237 - 9 Mar 2023

Cited by 8 | Viewed by 2309

Abstract

Saliva is gaining increasing attention as a source of biomarkers due to non-invasive and undemanding collection access. Extracellular vesicles (EVs) are nano-sized, cell-released particles that contain molecular information about their parent cells. In this study, we developed methods for saliva biomarker candidate identification using EV-isolation and proteomic evaluation. We used pooled saliva samples for assay development. EVs were isolated using membrane affinity-based methods followed by their characterization using nanoparticle tracking analysis and transmission electron microscopy. Subsequently, both saliva and saliva-EVs were successfully analyzed using proximity extension assay and label-free quantitative proteomics. Saliva-EVs had a higher purity than plasma-EVs, based on the expression of EV-proteins and albumin. The developed methods could be used for the analysis of individual saliva samples from amyotrophic lateral sclerosis (ALS) patients and controls (n = 10 each). The starting volume ranged from 2.1 to 4.9 mL and the amount of total isolated EV-proteins ranged from 5.1 to 42.6 µg. Although no proteins were significantly differentially expressed between the two groups, there was a trend for a downregulation of ZNF428 in ALS-saliva-EVs and an upregulation of IGLL1 in ALS saliva. In conclusion, we have developed a robust workflow for saliva and saliva-EV analysis and demonstrated its technical feasibility for biomarker discovery. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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10 pages, 1233 KiB

Open AccessArticle

Myelin Basic Protein in Oligodendrocyte-Derived Extracellular Vesicles as a Diagnostic and Prognostic Biomarker in Multiple Sclerosis: A Pilot Study

by Cristina Agliardi, Franca Rosa Guerini, Milena Zanzottera, Elisabetta Bolognesi, Silvia Picciolini, Domenico Caputo, Marco Rovaris, Maria Barbara Pasanisi and Mario Clerici

Int. J. Mol. Sci. 2023, 24(1), 894; https://doi.org/10.3390/ijms24010894 - 3 Jan 2023

Cited by 11 | Viewed by 3907

Abstract

Approximately 15% of multiple sclerosis (MS) patients develop a progressive form of disease from onset; this condition (primary progressive-PP) MS is difficult to diagnose and treat, and is associated with a poor prognosis. Extracellular vesicles (EVs) of brain origin isolated from blood and their protein cargoes could function as a biomarker of pathological conditions. We verified whether MBP and MOG content in oligodendrocytes-derived EVs (ODEVs) could be biomarkers of MS and could help in the differential diagnosis of clinical MS phenotypes. A total of 136 individuals (7 clinically isolated syndrome (CIS), 18 PPMS, 49 relapsing remitting (RRMS)) and 70 matched healthy controls (HC) were enrolled. ODEVs were enriched from serum by immune-capture with anti-MOG antibody; MBP and MOG protein cargoes were measured by ELISA. MBP concentration in ODEVs was significantly increased in CIS (p < 0.001), RRMS (p < 0.001) and PPMS (p < 0.001) compared to HC and was correlated with disease severity measured by EDSS and MSSS. Notably, MBP concentration in ODEVs was also significantly augmented in PPMS compared to RRMS (p = 0.004) and CIS (p = 0.03). Logistic regression and ROC analyses confirmed these results. A minimally invasive blood test measuring the concentration of MBP in ODEVs is a promising tool that could facilitate MS diagnosis. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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14 pages, 983 KiB

Open AccessCommunication

Rare Amyloid Precursor Protein Point Mutations Recapitulate Worldwide Migration and Admixture in Healthy Individuals: Implications for the Study of Neurodegeneration

by Paolo Abondio, Francesco Bruno, Amalia Cecilia Bruni and Donata Luiselli

Int. J. Mol. Sci. 2022, 23(24), 15871; https://doi.org/10.3390/ijms232415871 - 14 Dec 2022

Cited by 2 | Viewed by 1303

Abstract

Genetic discoveries related to Alzheimer’s disease and other dementias have been performed using either large cohorts of affected subjects or multiple individuals from the same pedigree, therefore disregarding mutations in the context of healthy groups. Moreover, a large portion of studies so far have been performed on individuals of European ancestry, with a remarkable lack of epidemiological and genomic data from underrepresented populations. In the present study, 70 single-point mutations on the APP gene in a publicly available genetic dataset that included 2504 healthy individuals from 26 populations were scanned, and their distribution was analyzed. Furthermore, after gametic phase reconstruction, a pairwise comparison of the segments surrounding the mutations was performed to reveal patterns of haplotype sharing that could point to specific cross-population and cross-ancestry admixture events. Eight mutations were detected in the worldwide dataset, with several of them being specific for a single individual, population, or macroarea. Patterns of segment sharing reflected recent historical events of migration and admixture possibly linked to colonization campaigns. These observations reveal the population dynamics of the considered APP mutations in worldwide human groups and support the development of ancestry-informed screening practices for the improvement of precision and personalized approaches to neurodegeneration and dementia. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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12 pages, 644 KiB

Open AccessArticle

Association of LTA and SOD Gene Polymorphisms with Cerebral White Matter Hyperintensities in Migraine Patients

by Patrizia Ferroni, Raffaele Palmirotta, Gabriella Egeo, Cinzia Aurilia, Maria Giovanna Valente, Antonella Spila, Alberto Pierallini, Piero Barbanti and Fiorella Guadagni

Int. J. Mol. Sci. 2022, 23(22), 13781; https://doi.org/10.3390/ijms232213781 - 9 Nov 2022

Cited by 2 | Viewed by 1780

Abstract

White matter hyperintensities (WMHs) in migraine could be related to inflammatory and antioxidant events. The aim of this study is to verify whether migraine patients with WMHs carry a genetic pro-inflammatory/pro-oxidative status. To test this hypothesis, we analyzed lymphotoxin alpha (LTA; rs2071590T and rs2844482G) and superoxide dismutase 1 (SOD1; rs2234694C) and 2 (SOD2; rs4880T) gene polymorphisms (SNPs) in 370 consecutive patients affected by episodic (EM; n = 251) and chronic (CM; n = 119) migraine and in unrelated healthy controls (n = 100). Brain magnetic resonance was available in 183/370 patients. The results obtained show that genotypes and allele frequencies for all tested SNPs did not differ between patients and controls. No association was found between single SNPs or haplotypes and sex, migraine type, cardiovascular risk factors or disorders. Conversely, the LTA rs2071590T (OR = 2.2) and the SOD1 rs2234694C (OR = 4.9) alleles were both associated with WMHs. A four-loci haplotype (TGCT haplotype: rs2071590T/rs2844482G/rs2234694C/rs4880T) was significantly more frequent in migraineurs with WMHs (7 of 38) compared to those without WMHs (4 of 134; OR = 8.7). We may, therefore, conclude by suggesting that that an imbalance between pro-inflammatory/pro-oxidative and antioxidant events in genetically predisposed individuals may influence the development of WMHs. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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11 pages, 1127 KiB

Open AccessArticle

Cerebrospinal Fluid Alpha-Synuclein Improves the Differentiation between Dementia with Lewy Bodies and Alzheimer’s Disease in Clinical Practice

by Matthieu Lilamand, Josué Clery, Agathe Vrillon, François Mouton-Liger, Emmanuel Cognat, Sinead Gaubert, Claire Hourregue, Matthieu Martinet, Julien Dumurgier, Jacques Hugon, Elodie Bouaziz-Amar and Claire Paquet

Int. J. Mol. Sci. 2022, 23(21), 13488; https://doi.org/10.3390/ijms232113488 - 4 Nov 2022

Viewed by 1618

Abstract

Background: Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer’s disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. Methods: In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. Results: We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p < 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p < 0.01) but not with hippocampal atrophy or white matter lesions. Conclusion: CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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13 pages, 1049 KiB

Open AccessArticle

Elevated Cerebrospinal Fluid Proteins and Albumin Determine a Poor Prognosis for Spinal Amyotrophic Lateral Sclerosis

by Abdelilah Assialioui, Raúl Domínguez, Isidro Ferrer, Pol Andrés-Benito and Mónica Povedano

Int. J. Mol. Sci. 2022, 23(19), 11063; https://doi.org/10.3390/ijms231911063 - 21 Sep 2022

Cited by 7 | Viewed by 2427

Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease, both in its onset phenotype and in its rate of progression. The aim of this study was to establish whether the dysfunction of the blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB) measured through cerebrospinal fluid (CSF) proteins and the albumin-quotient (QAlb) are related to the speed of disease progression. An amount of 246 patients diagnosed with ALS were included. CSF and serum samples were determined biochemically for different parameters. Survival analysis based on phenotype shows higher probability of death for bulbar phenotype compared to spinal phenotype (p-value: 0.0006). For the effect of CSF proteins, data shows an increased risk of death for spinal ALS patients as the value of CSF proteins increases. The same model replicated for CSF albumin yielded similar results. Statistical models determined that the lowest cut-off value for CSF proteins able to differentiate patients with a good prognosis and worse prognosis corresponds to CSF proteins ≥ 0.5 g/L (p-value: 0.0189). For the CSF albumin, the QAlb ≥0.65 is associated with elevated probability of death (p-value: 0.0073). High levels of QAlb are a bad prognostic indicator for the spinal phenotype, in addition to high CSF proteins levels that also act as a marker of poor prognosis. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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Review

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13 pages, 1033 KiB

Open AccessReview

Gender Differences in Cortisol and Cortisol Receptors in Depression: A Narrative Review

by Chuin Hau Teo, Ally Chai Hui Wong, Rooba Nair Sivakumaran, Ishwar Parhar and Tomoko Soga

Int. J. Mol. Sci. 2023, 24(8), 7129; https://doi.org/10.3390/ijms24087129 - 12 Apr 2023

Cited by 5 | Viewed by 4153

Abstract

Stress is known to have a significant impact on mental health. While gender differences can be found in stress response and mental disorders, there are limited studies on the neuronal mechanisms of gender differences in mental health. Here, we discuss gender and cortisol in depression as presented by recent clinical studies, as well as gender differences in the role of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in stress-associated mental disorders. When examining clinical studies drawn from PubMed/MEDLINE (National Library of Medicine) and EMBASE, salivary cortisol generally showed no gender correlation. However, young males were reported to show heightened cortisol reactivity compared to females of similar age in depression. Pubertal hormones, age, early life stressors, and types of bio-samples for cortisol measurement affected the recorded cortisol levels. The role of GRs and MRs in the HPA axis could be different between males and females during depression, with increased HPA activity and upregulated MR expression in male mice, while the inverse happened in female mice. The functional heterogeneity and imbalance of GRs and MRs in the brain may explain gender differences in mental disorders. This knowledge and understanding will support the development of gender-specific diagnostic markers involving GRs and MRs in depression. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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31 pages, 8332 KiB

Open AccessReview

Ubiquitin Proteasome Gene Signatures in Ependymoma Molecular Subtypes

by Jerry Vriend, Thatchawan Thanasupawat, Namita Sinha and Thomas Klonisch

Int. J. Mol. Sci. 2022, 23(20), 12330; https://doi.org/10.3390/ijms232012330 - 15 Oct 2022

Cited by 2 | Viewed by 2240

Abstract

The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently, a comprehensive review of the role of the UPS in ependymoma (EPN) brain tumors is lacking but may provide valuable new information on cellular networks specific to different EPN subtypes and reveal future therapeutic targets. We have reviewed publicly available EPN gene transcription datasets encoding components of the UPS pathway. Reactome analysis of these data revealed genes and pathways that were able to distinguish different EPN subtypes with high significance. We identified differential transcription of several genes encoding ubiquitin E2 conjugases associated with EPN subtypes. The expression of the E2 conjugase genes UBE2C, UBE2S, and UBE2I was elevated in the ST_EPN_RELA subtype. The UBE2C and UBE2S enzymes are associated with the ubiquitin ligase anaphase promoting complex (APC/c), which regulates the degradation of substrates associated with cell cycle progression, whereas UBE2I is a Sumo-conjugating enzyme. Additionally, elevated in ST_EPN_RELA were genes for the E3 ligase and histone deacetylase HDAC4 and the F-box cullin ring ligase adaptor FBX031. Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome Pathways associated with differentially expressed genes for E3 ligases and their adaptors included antigen presentation, neddylation, sumoylation, and the APC/c complex. Our analysis provides several UPS associated factors that may be attractive markers and future therapeutic targets for the subtype-specific treatment of EPN patients. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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37 pages, 4734 KiB

Open AccessReview

Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene

by Jaya Bagaria, Eva Bagyinszky and Seong Soo A. An

Int. J. Mol. Sci. 2022, 23(18), 10970; https://doi.org/10.3390/ijms231810970 - 19 Sep 2022

Cited by 22 | Viewed by 5260

Abstract

Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer’s disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, and calcium metabolism. Several motifs and residues have been identified in PSEN1, which may play a significant role in γ-secretase mechanisms, such as the WNF, GxGD, and PALP motifs. More than 300 mutations have been described in PSEN1; however, the clinical phenotypes related to these mutations may be diverse. In addition to classical EOAD, patients with PSEN1 mutations regularly present with atypical phenotypic symptoms, such as spasticity, seizures, and visual impairment. In vivo and in vitro studies were performed to verify the effect of PSEN1 mutations on EOAD. The pathogenic nature of PSEN1 mutations can be categorized according to the ACMG-AMP guidelines; however, some mutations could not be categorized because they were detected only in a single case, and their presence could not be confirmed in family members. Genetic modifiers, therefore, may play a critical role in the age of disease onset and clinical phenotypes of PSEN1 mutations. This review introduces the role of PSEN1 in γ-secretase, the clinical phenotypes related to its mutations, and possible significant residues of the protein. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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18 pages, 1148 KiB

Open AccessReview

LRRK2 and Proteostasis in Parkinson’s Disease

by María Dolores Pérez-Carrión, Inmaculada Posadas, Javier Solera and Valentín Ceña

Int. J. Mol. Sci. 2022, 23(12), 6808; https://doi.org/10.3390/ijms23126808 - 18 Jun 2022

Cited by 6 | Viewed by 2711

Abstract

Parkinson’s disease is a neurodegenerative condition initially characterized by the presence of tremor, muscle stiffness and impaired balance, with the deposition of insoluble protein aggregates in Lewy’s Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson’s disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson’s disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of α-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson’s disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin–proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson’s disease through the regulation of LRRK2, using small molecules or LRRK2 silencing. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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