Special Issue "Parkinson's Disease: Genetics and Pathogenesis"

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

Deadline for manuscript submissions: 1 January 2022.

Special Issue Editors

Dr. Suzanne Lesage
E-Mail Website
Guest Editor
Sorbonne Université, Institut du Cerveau—Paris Brain Institute—ICM, INSERM, CNRS, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, CIC Neurosciences, 75013 Paris, France
Interests: genetics of Parkinson’s disease and other neurodegenerative disorders; next-generation sequencing; exomes; whole genomes; transcriptomics; genome-wide association studies
Dr. Joanne Trinh
E-Mail Website
Guest Editor
Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany
Interests: Parkinson's genetics; movement disorders; GWAS; monogenic diseases; genetic modifiers; long-read sequencing; genomes; exomes; genotype-phenotype correlations

Special Issue Information

Dear Colleagues,

Parkinson's disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65. Although the disease remains defined clinically by its cardinal motor manifestations and pathologically by midbrain dopaminergic cell loss in association with intraneuronal Lewy bodies, the molecular mechanisms that lead to neurodegeneration remain elusive. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. The last 25 years have seen great progress towards understanding the genetic basis of this disease, with the identification of disease-causing genes. At least 23 loci and 13 genes clearly linked to inherited forms of Parkinsonism have been identified to date; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. Impressive sets of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. By contrast, alpha-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. The impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships is the main challenge for the next decade. In this issue, emerging lessons on PD pathogenesis from clinical, pathological, and genetic studies towards a unified concept of the disorder will be provided, which may accelerate the design and testing of the next generation of PD therapies.

Dr. Suzanne Lesage
Dr. Joanne Trinh
Guest Editors

Manuscript Submission Information

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Keywords

  • Parkinson’s disease
  • Genetics
  • Molecular pathogenesis
  • Pathways
  • Physiopathological mechanisms
  • Mitochondrial dysfunction
  • Parkin
  • PINK1
  • SNCA
  • LRRK2
  • Animal model
  • Cell model

Published Papers (3 papers)

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Research

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Article
Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease
Genes 2021, 12(10), 1545; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101545 - 29 Sep 2021
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Abstract
Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson’s disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. [...] Read more.
Mutations of the GBA gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for Parkinson’s disease (PD) with frequency between 5% and 20% across the world. N370S and L444P are the two most common mutations in the GBA gene. PD carriers of severe mutation L444P in the GBA gene is characterized by the earlier age at onset compared to N370S. Not every carrier of GBA mutations develop PD during one’s lifetime. In the current study we aimed to find common gene expression signatures in PD associated with mutation in the GBA gene (GBA-PD) using RNA-seq. We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
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Article
C9orf72-G4C2 Intermediate Repeats and Parkinson’s Disease; A Data-Driven Hypothesis
Genes 2021, 12(8), 1210; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081210 - 05 Aug 2021
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Abstract
Pathogenic C9orf72-G4C2 repeat expansions are associated with ALS/FTD, but not with Parkinson’s disease (PD); yet the possible link between intermediate repeat lengths and PD remains inconclusive. We aim to study the potential involvement of these repeats in PD. The [...] Read more.
Pathogenic C9orf72-G4C2 repeat expansions are associated with ALS/FTD, but not with Parkinson’s disease (PD); yet the possible link between intermediate repeat lengths and PD remains inconclusive. We aim to study the potential involvement of these repeats in PD. The number of C9orf72-repeats were determined by flanking and repeat-primed PCR assays, and the risk-haplotype was determined by SNP-array. Their association with PD was assessed in a stratified manner: in PD-patients-carriers of mutations in LRRK2, GBA, or SMPD1 genes (n = 388), and in PD-non-carriers (NC, n = 718). Allelic distribution was significantly different only in PD-NC compared to 600 controls when looking both at the allele with higher repeat’s size (p = 0.034) and at the combined number of repeats from both alleles (p = 0.023). Intermediate repeats (20–60 repeats) were associated with PD in PD-NC patients (p = 0.041; OR = 3.684 (CI 1.05–13.0)) but not in PD-carriers (p = 0.684). The C9orf72 risk-haplotype, determined in a subgroup of 588 PDs and 126 controls, was observed in higher frequency in PD-NC (dominant model, OR = 1.71, CI 1.04–2.81, p = 0.0356). All 19 alleles within the risk-haplotype were associated with higher C9orf72 RNA levels according to the GTEx database. Based on our data, we suggest a model in which intermediate repeats are a risk factor for PD in non-carriers, driven not only by the number of repeats but also by the variants’ genotypes within the risk-haplotype. Further studies are needed to elucidate this possible role of C9orf72 in PD pathogenesis. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
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Review

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Review
Mapping the Diverse and Inclusive Future of Parkinson’s Disease Genetics and Its Widespread Impact
by , , and
Genes 2021, 12(11), 1681; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111681 (registering DOI) - 23 Oct 2021
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Abstract
Over the last decades, genetics has been the engine that has pushed us along on our voyage to understand the etiology of Parkinson’s disease (PD). Although a large number of risk loci and causative mutations for PD have been identified, it is clear [...] Read more.
Over the last decades, genetics has been the engine that has pushed us along on our voyage to understand the etiology of Parkinson’s disease (PD). Although a large number of risk loci and causative mutations for PD have been identified, it is clear that much more needs to be done to solve the missing heritability mystery. Despite remarkable efforts, as a field, we have failed in terms of diversity and inclusivity. The vast majority of genetic studies in PD have focused on individuals of European ancestry, leading to a gap of knowledge on the existing genetic differences across populations and PD as a whole. As we move forward, shedding light on the genetic architecture contributing to PD in non-European populations is essential, and will provide novel insight into the generalized genetic map of the disease. In this review, we discuss how better representation of understudied ancestral groups in PD genetics research requires addressing and resolving all the challenges that hinder the inclusion of these populations. We further provide an overview of PD genetics in the clinics, covering the current challenges and limitations of genetic testing and counseling. Finally, we describe the impact of worldwide collaborative initiatives in the field, shaping the future of the new era of PD genetics as we advance in our understanding of the genetic architecture of PD. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1. Involvement of epigenetic alterations in Parkinson's disease

2. Elucidating genomic and transcriptomic hexanucleotide repeat number and methylation in the X-linked
dystonia-parkinsonism-relevant retrotransposon insertion by Nanopore sequencing

3. Comparative genetic analysis of Parkinson`s disease and Dystonia using disease-specific Polygenic Risk Scores

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