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Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition
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Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: 15 May 2025 | Viewed by 9111

Special Issue Editor

Dr. Claudia Ricci

E-Mail Website
Guest Editor
Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
Interests: neurogenetics; motor neuron diseases; amyotrophic lateral sclerosis; cerebral cavernous malformations; genotype-phenotype correlations; gene variant consequences; microRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genetic factors are key players in the pathogenesis of several neurodegenerative diseases, acting both as monogenic causes in inherited diseases and modulatory factors in multifactorial/sporadic diseases. With the recent advances in cost-effective genetic analyses, knolwledge of the genetic bases of several neurodegenerative disorders has expanded significantly great strides, improving our understanding of the mechanisms underpinning the pathogenesis of these conditions.

Neurodegenerative diseases display a certain degree of genetic heterogeneity; in other words, the presentation and severity of disease may vary from individual to individual. In some cases, the same phenotype can be determined according to different variants in different genes. On the other hand, the same mutation may be associated with phenotypic heterogeneity, also in the same family. However, in some cases, a specific variant may be related to a uniform phenotype, proving helpful for diagnostic and prognostic aims. In the precision medicine era, the enhanced characterization of genotype–phenotype correlations may allow us to improve therapeutic approaches, evaluate individual drug responses and guide gene-focused clinical trials.

This Special Issue is the second edition of the Special Issue "Study on Genotypes and Phenotypes of Neurodegenerative Diseases", and aims to provide an overview of this field. Contributions related, but not limited to, Alzheimer's disease and other dementias, Parkinson's disease, and motor neurone diseases are welcome, including original research articles and reviews.

Dr. Claudia Ricci
Guest Editor

Manuscript Submission Information

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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. Genes 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

  • neurodegenerative diseases
  • genetic variants
  • genotype
  • phenotype
  • genotype–phenotype correlations

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Published Papers (5 papers)

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Research

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20 pages, 14607 KiB  
Article
Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial Alzheimer’s Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and Estrogenic Treatments
by Mario Díaz
Genes 2024, 15(6), 810; https://doi.org/10.3390/genes15060810 - 19 Jun 2024
Cited by 1 | Viewed by 1710
Abstract
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer’s disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered [...] Read more.
Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer’s disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer’s disease neuropathology. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition)
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11 pages, 734 KiB  
Article
Spectrum of ERCC6-Related Cockayne Syndrome (Type B): From Mild to Severe Forms
by Jacopo Sartorelli, Lorena Travaglini, Marina Macchiaiolo, Giacomo Garone, Michaela Veronika Gonfiantini, Davide Vecchio, Lorenzo Sinibaldi, Flaminia Frascarelli, Viola Ceccatelli, Sara Petrillo, Fiorella Piemonte, Gabriele Piccolo, Antonio Novelli, Daniela Longo, Stefano Pro, Adele D’Amico, Enrico Silvio Bertini and Francesco Nicita
Genes 2024, 15(4), 508; https://doi.org/10.3390/genes15040508 - 18 Apr 2024
Cited by 1 | Viewed by 2151
Abstract
(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed [...] Read more.
(1) Background: Cockayne syndrome (CS) is an ultra-rare multisystem disorder, classically subdivided into three forms and characterized by a clinical spectrum without a clear genotype-phenotype correlation for both the two causative genes ERCC6 (CS type B) and ERCC8 (CS type A). We assessed this, presenting a series of patients with genetically confirmed CSB. (2) Materials and Methods: We retrospectively collected demographic, clinical, genetic, neuroimaging, and serum neurofilament light-chain (sNFL) data about CSB patients; diagnostic and severity scores were also determined. (3) Results: Data of eight ERCC6/CSB patients are presented. Four patients had CS I, three patients CS II, and one patient CS III. Various degrees of ataxia and spasticity were cardinal neurologic features, with variably combined systemic characteristics. Mean age at diagnosis was lower in the type II form, in which classic CS signs were more evident. Interestingly, sNFL determination appeared to reflect clinical classification. Two novel premature stop codon and one novel missense variants were identified. All CS I subjects harbored the p.Arg735Ter variant; the milder CS III subject carried the p.Leu764Ser missense change. (4) Conclusion: Our work confirms clinical variability also in the ERCC6/CSB type, where manifestations may range from severe involvement with prenatal or neonatal onset to normal psychomotor development followed by progressive ataxia. We propose, for the first time in CS, sNFL as a useful peripheral biomarker, with increased levels compared to currently available reference values and with the potential ability to reflect disease severity. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition)
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16 pages, 2290 KiB  
Article
Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions
by Thea J. Rosewood, Kwangsik Nho, Shannon L. Risacher, Sujuan Gao, Li Shen, Tatiana Foroud, Andrew J. Saykin and on behalf of the Alzheimer’s Disease Neuroimaging Initiative
Genes 2023, 14(11), 2010; https://doi.org/10.3390/genes14112010 - 27 Oct 2023
Cited by 1 | Viewed by 2221
Abstract
The underlying genetic susceptibility for Alzheimer’s disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD [...] Read more.
The underlying genetic susceptibility for Alzheimer’s disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition)
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Review

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18 pages, 356 KiB  
Review
Insights on the Genetic and Phenotypic Complexities of Optic Neuropathies
by Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni and Caterina Gagliano
Genes 2024, 15(12), 1559; https://doi.org/10.3390/genes15121559 - 29 Nov 2024
Cited by 1 | Viewed by 1214
Abstract
Background/Objectives: Optic neuropathies are a category of illnesses that ultimately cause damage to the optic nerve, leading to vision impairment and possible blindness. Disorders such as dominant optic atrophy (DOA), Leber hereditary optic neuropathy (LHON), and glaucoma demonstrate intricate genetic [...] Read more.
Background/Objectives: Optic neuropathies are a category of illnesses that ultimately cause damage to the optic nerve, leading to vision impairment and possible blindness. Disorders such as dominant optic atrophy (DOA), Leber hereditary optic neuropathy (LHON), and glaucoma demonstrate intricate genetic foundations and varied phenotypic manifestations. This narrative review study seeks to consolidate existing knowledge on the genetic and molecular mechanisms underlying ocular neuropathies, examine genotype-phenotype correlations, and assess novel therapeutic options to improve diagnostic and treatment methodologies. Methods: A systematic literature review was performed in October 2024, utilizing PubMed, Medline, the Cochrane Library, and ClinicalTrials.gov. Search terms encompassed “optic neuropathy”, “genetic variants”, “LHON”, “DOA”, “glaucoma”, and “molecular therapies”. Studies were chosen according to established inclusion criteria, concentrating on the genetic and molecular dimensions of optic neuropathies and their therapeutic ramifications. Results: The results indicate that DOA and LHON are mostly associated with the mitochondrial dysfunction resulting from pathogenic variants in nuclear genes, mainly OPA1, and mitochondrial DNA (mtDNA) genes, respectively. Glaucoma, especially its intricate variants, is linked to variants in genes like MYOC, OPTN, and TBK1. Molecular mechanisms, such as oxidative stress and inflammatory modulation, are pivotal in disease progression. Innovative therapeutics, including gene therapy, RNA-based treatments, and antioxidants such as idebenone, exhibit promise for alleviating optic nerve damage and safeguarding vision. Conclusions: Genetic and molecular investigations have markedly enhanced our comprehension of ocular neuropathies. The amalgamation of genetic and phenotypic data is essential for customized medical strategies. Additional research is required to enhance therapeutic strategies and fill the gaps in our understanding of the underlying pathophysiology. This interdisciplinary approach shows potential for enhancing patient outcomes in ocular neuropathies. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition)

Other

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90 pages, 16197 KiB  
Perspective
Production of Amyloid-β in the Aβ-Protein-Precursor Proteolytic Pathway Is Discontinued or Severely Suppressed in Alzheimer’s Disease-Affected Neurons: Contesting the ‘Obvious’
by Vladimir Volloch and Sophia Rits-Volloch
Genes 2025, 16(1), 46; https://doi.org/10.3390/genes16010046 - 2 Jan 2025
Viewed by 982
Abstract
A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer’s disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer’s research field. The present Perspective challenges this assumption. It analyses the [...] Read more.
A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer’s disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer’s research field. The present Perspective challenges this assumption. It analyses the relevant empirical data and reaches an unexpected conclusion, namely that in AD-afflicted neurons, the production of AβPP-derived Aβ is either discontinued or severely suppressed, a concept that, if proven, would fundamentally change our understanding of the disease. This suppression, effectively self-suppression, occurs in the context of the global inhibition of the cellular cap-dependent protein synthesis as a consequence of the neuronal integrated stress response (ISR) elicited by AβPP-derived intraneuronal Aβ (iAβ; hence self-suppression) upon reaching certain levels. Concurrently with the suppression of the AβPP proteolytic pathway, the neuronal ISR activates in human neurons, but not in mouse neurons, the powerful AD-driving pathway generating the C99 fragment of AβPP independently of AβPP. The present study describes molecular mechanisms potentially involved in these phenomena, propounds novel approaches to generate transgenic animal models of AD, advocates for the utilization of human neuronal cells-based models of the disease, makes verifiable predictions, suggests experiments designed to validate the proposed concept, and considers its potential research and therapeutic implications. Remarkably, it opens up the possibility that the conventional production of AβPP, BACE enzymes, and γ-secretase components is also suppressed under the neuronal ISR conditions in AD-affected neurons, resulting in the dyshomeostasis of AβPP. It follows that whereas conventional AD is triggered by AβPP-derived iAβ accumulated to the ISR-eliciting levels, the disease, in its both conventional and unconventional (triggered by the neuronal ISR-eliciting stressors distinct from iAβ) forms, is driven not (or not only) by iAβ produced in the AβPP-independent pathway, as we proposed previously, but mainly, possibly exclusively, by the C99 fragment generated independently of AβPP and not cleaved at the γ-site due to the neuronal ISR-caused deficiency of γ-secretase (apparently, the AD-driving “substance X” predicted in our previous study), a paradigm consistent with a dictum by George Perry that Aβ is “central but not causative” in AD. The proposed therapeutic strategies would not only deplete the driver of the disease and abrogate the AβPP-independent production of C99 but also reverse the neuronal ISR and ameliorate the AβPP dyshomeostasis, a potentially significant contributor to AD pathology. Full article
(This article belongs to the Special Issue Study on Genotypes and Phenotypes of Neurodegenerative Diseases—2nd Edition)
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