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Translating Genetic Discoveries in Neurodegenerative Diseases Research

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 30609

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Special Issue Editors

Prof. Dr. Ornit Chiba-Falek

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Guest Editor

Division of Translational Brain Sciences, Department of Neurology & Pathology, and the Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27710, USA
Interests: age-related neurodegenerative diseases; neurogenetics; functional genomics; regulation of gene expression; precision medicine and ‘next generation’ gene therapy approaches for Alzheimer’s-Parkinson’s
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Dr. Boris Kantor

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Guest Editor

Director of Viral Vector Core, Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA
Interests: gene therapy; neurodegenerative diseases; gene regulation; epigenetic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A major challenge in the post-genome wide association study (GWAS) era of age-related neurodegenerative diseases (NDDs), including late-onset Alzheimer’s disease (LOAD) and Parkinson’s disease (PD), is progressing from the identified genetic associations to disease mechanism. It has been over a decade since LOAD- and PD-GWAS studies first emerged. However, the actual genes involved in the disease, the causal variants, and the molecular mechanism by which they exert their pathogenic effect remain largely unknown. Most disease-associated SNPs are in noncoding regions, which are likely impacting disease-relevant brain regulatory elements that control expression of disease risk genes. Current studies aim to untangle the genetic complexity and genomic architecture of NDDs and to translate genetic association discoveries to causal mechanisms of disease. These studies integrate characterization of human brain tissues, in silico, in vitro, and in vivo approaches. Advancing the understanding of NDDs’ genetic complexity and deciphering the regulatory elements and the corresponding genes mediating NDD risk will be translational by refining polygenic risk scores (PRS) based on functional data and identifying novel therapeutic targets for these devastating diseases which manipulate dysregulated genes.

The topics we would like to cover include but are not limited to:

Whole genome multi-omics profiling of disease and healthy brains;
GWAS for disease endophenotypes;
Mechanistic insight into the function of disease-established key genes including: APOE, SNCA, LRRK2;
Development of animal models;
Establishment of hiPSC-derived models;
Construction of PRS and PHS;
Gene therapy appraoches such as ASO and genome editting.

Prof. Ornit Chiba-Falek
Dr. Boris Kantor
Guest Editors

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Keywords

Alzheimer’s
Parkinson’s
Multi-omics profiling
hiPSC
Animal models
Neurodegeneration
Gene therapy
Polygenic risk scores and polygenic hazards scores

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Published Papers (6 papers)

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Research

Jump to: Review

16 pages, 12829 KiB

Open AccessArticle

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

by Sulev Koks, Abigail L. Pfaff, Vivien J. Bubb and John P. Quinn

Int. J. Mol. Sci. 2021, 22(12), 6319; https://doi.org/10.3390/ijms22126319 - 12 Jun 2021

Cited by 11 | Viewed by 2768

Abstract

Transposable elements (TEs) are repetitive elements that belong to a variety of functional classes and have an important role in shaping genome evolution. Around 50% of the human genome contains TEs, and they have been termed the “dark matter” of the genome because relatively little is known about their function. While TEs have been shown to participate in aberrant gene regulation and the pathogenesis of diseases, only a few studies have explored the systemic effect of TEs on gene expression. In the present study, we analysed whole genome sequences and blood whole transcriptome data from 570 individuals within the Parkinson’s Progressive Markers Initiative (PPMI) cohort to identify expression quantitative trait loci (eQTL) regulating genome-wide gene expression associated with TEs. We identified 2132 reference TEs that were polymorphic for their presence or absence in our study cohort. The presence or absence of the TE element could change the expression of the gene or gene clusters from zero to tens of thousands of copies of RNA. The main finding is that many TEs possess very strong regulatory effects, and they have the potential to modulate large genetic networks with hundreds of target genes over the genome. We illustrate the plethora of regulatory mechanisms using examples of their action at the HLA gene cluster and data showing different TEs’ convergence to modulate WFS1 gene expression. In conclusion, the presence or absence of polymorphisms of TEs has an eminent genome-wide regulatory function with large effect size at the level of the whole transcriptome. The role of TEs in explaining, in part, the missing heritability for complex traits is convincing and should be considered. Full article

(This article belongs to the Special Issue Translating Genetic Discoveries in Neurodegenerative Diseases Research)

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15 pages, 2799 KiB

Open AccessArticle

Expression Levels of an Alpha-Synuclein Transcript in Blood May Distinguish between Early Dementia with Lewy Bodies and Parkinson’s Disease

by Laura Marsal-García, Aintzane Urbizu, Laura Arnaldo, Jaume Campdelacreu, Dolores Vilas, Lourdes Ispierto, Jordi Gascón-Bayarri, Ramón Reñé, Ramiro Álvarez and Katrin Beyer

Int. J. Mol. Sci. 2021, 22(2), 725; https://doi.org/10.3390/ijms22020725 - 13 Jan 2021

Cited by 9 | Viewed by 4158

Abstract

Lewy body diseases (LBD) including dementia with Lewy bodies (DLB) and Parkinson disease (PD) are characterized by alpha-synuclein pathology. DLB is difficult to diagnose and peripheral biomarkers are urgently needed. Therefore, we analyzed the expression of five alpha-synuclein gene (SNCA) transcripts, SNCAtv1, SNCAtv2, SNCAtv3, SNCA126, and SNCA112, in 45 LBD and control temporal cortex samples and in the blood of 72 DLB, 59 PD, and 54 control subjects. The results revealed overexpression of SNCAtv1 and SNCA112 in DLB, and SNCAtv2 in PD temporal cortices. In DLB blood, diminution of all SNCA transcripts was observed. SNCAtv1 and SNCAtv2 were diminished in PD with disease onset before 70 years. SNCAtv3, driven by its own promoter, showed opposite expression in early DLB and PD, suggesting that its amount may be an early, DLB specific biomarker. Correlation between blood transcript levels and disease duration was positive in DLB and negative in PD, possibly reflecting differences in brain alpha-synuclein aggregation rates associated with differences in disease courses. In conclusion, SNCA transcripts showed a disease-specific increase in the brain and were diminished in blood of LBD patients. SNCAtv3 expression was decreased in early DLB and increased in early PD and could be a biomarker for early DLB diagnosis. Full article

(This article belongs to the Special Issue Translating Genetic Discoveries in Neurodegenerative Diseases Research)

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Review

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13 pages, 1055 KiB

Open AccessReview

Parkinson’s Disease-Related Genes and Lipid Alteration

by Milena Fais, Antonio Dore, Manuela Galioto, Grazia Galleri, Claudia Crosio and Ciro Iaccarino

Int. J. Mol. Sci. 2021, 22(14), 7630; https://doi.org/10.3390/ijms22147630 - 16 Jul 2021

Cited by 33 | Viewed by 4888

Abstract

Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein accumulation—and finally neuronal death. Full article

(This article belongs to the Special Issue Translating Genetic Discoveries in Neurodegenerative Diseases Research)

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15 pages, 1653 KiB

Open AccessReview

APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer’s

by Anna Yang, Boris Kantor and Ornit Chiba-Falek

Int. J. Mol. Sci. 2021, 22(3), 1244; https://doi.org/10.3390/ijms22031244 - 27 Jan 2021

Cited by 32 | Viewed by 6055

Abstract

Alzheimer’s disease (AD) has a critical unmet medical need. The consensus around the amyloid cascade hypothesis has been guiding pre-clinical and clinical research to focus mainly on targeting beta-amyloid for treating AD. Nevertheless, the vast majority of the clinical trials have repeatedly failed, prompting the urgent need to refocus on other targets and shifting the paradigm of AD drug development towards precision medicine. One such emerging target is apolipoprotein E (APOE), identified nearly 30 years ago as one of the strongest and most reproduceable genetic risk factor for late-onset Alzheimer’s disease (LOAD). An exploration of APOE as a new therapeutic culprit has produced some very encouraging results, proving that the protein holds promise in the context of LOAD therapies. Here, we review the strategies to target APOE based on state-of-the-art technologies such as antisense oligonucleotides, monoclonal antibodies, and gene/base editing. We discuss the potential of these initiatives in advancing the development of novel precision medicine therapies to LOAD. Full article

(This article belongs to the Special Issue Translating Genetic Discoveries in Neurodegenerative Diseases Research)

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24 pages, 885 KiB

Open AccessReview

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism

by Vinita G. Chittoor-Vinod, R. Jeremy Nichols and Birgitt Schüle

Int. J. Mol. Sci. 2021, 22(3), 1045; https://doi.org/10.3390/ijms22031045 - 21 Jan 2021

Cited by 16 | Viewed by 4561

Abstract

Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson’s disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2, p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer’s pathology, hailing LRRK2 parkinsonism as the “Rosetta stone” of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors—either increasing toxicity or providing resilience—will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and LRRK2-related neurodegeneration. Full article

(This article belongs to the Special Issue Translating Genetic Discoveries in Neurodegenerative Diseases Research)

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32 pages, 2174 KiB

Open AccessReview

The Role of Alpha-Synuclein and Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders

by C. Alejandra Morato Torres, Zinah Wassouf, Faria Zafar, Danuta Sastre, Tiago Fleming Outeiro and Birgitt Schüle

Int. J. Mol. Sci. 2020, 21(16), 5724; https://doi.org/10.3390/ijms21165724 - 10 Aug 2020

Cited by 40 | Viewed by 7238

Abstract

Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration. Full article

(This article belongs to the Special Issue Translating Genetic Discoveries in Neurodegenerative Diseases Research)

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