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: closed (15 July 2022) | Viewed by 45981

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors


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

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

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. 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

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

Published Papers (13 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

4 pages, 198 KiB  
Editorial
Special Issue “Parkinson’s Disease: Genetics and Pathogenesis”
by Suzanne Lesage and Joanne Trinh
Genes 2023, 14(3), 737; https://doi.org/10.3390/genes14030737 - 17 Mar 2023
Cited by 2 | Viewed by 1530
Abstract
Parkinson’s disease (PD) is a common and incurable neurodegenerative disease, affecting 1% of the population over the age of 65 [...] Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)

Research

Jump to: Editorial, Review

11 pages, 289 KiB  
Article
Relationship between Substantia Nigra Neuromelanin Imaging and Dual Alpha-Synuclein Labeling of Labial Minor in Salivary Glands in Isolated Rapid Eye Movement Sleep Behavior Disorder and Parkinson’s Disease
by Graziella Mangone, Marion Houot, Rahul Gaurav, Susana Boluda, Nadya Pyatigorskaya, Alizé Chalancon, Danielle Seilhean, Annick Prigent, Stéphane Lehéricy, Isabelle Arnulf, Jean-Christophe Corvol, Marie Vidailhet, Charles Duyckaerts and Bertrand Degos
Genes 2022, 13(10), 1715; https://doi.org/10.3390/genes13101715 - 24 Sep 2022
Cited by 7 | Viewed by 1822
Abstract
We investigated the presence of misfolded alpha-Synuclein (α-Syn) in minor salivary gland biopsies in relation to substantia nigra pars compacta (SNc) damage measured using magnetic resonance imaging in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and Parkinson’s disease (PD) as [...] Read more.
We investigated the presence of misfolded alpha-Synuclein (α-Syn) in minor salivary gland biopsies in relation to substantia nigra pars compacta (SNc) damage measured using magnetic resonance imaging in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and Parkinson’s disease (PD) as compared to healthy controls. Sixty-one participants (27 PD, 16 iRBD, and 18 controls) underwent a minor salivary gland biopsy and were scanned using a 3 Tesla MRI. Deposits of α-Syn were found in 15 (55.6%) PD, 7 (43.8%) iRBD, and 7 (38.9%) controls using the anti-aggregated α-Syn clone 5G4 antibody and in 4 (14.8%) PD, 3 (18.8%) iRBD and no control using the purified mouse anti-α-Syn clone 42 antibody. The SNc damages obtained using neuromelanin-sensitive imaging did not differ between the participants with versus without α-Syn deposits (irrespective of the antibodies and the disease group). Our study indicated that the α-Syn detection in minor salivary gland biopsies lacks sensitivity and specificity and does not correlate with the SNc damage, suggesting that it cannot be used as a predictive or effective biomarker for PD. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
21 pages, 540 KiB  
Article
A Machine Learning Approach to Parkinson’s Disease Blood Transcriptomics
by Ester Pantaleo, Alfonso Monaco, Nicola Amoroso, Angela Lombardi, Loredana Bellantuono, Daniele Urso, Claudio Lo Giudice, Ernesto Picardi, Benedetta Tafuri, Salvatore Nigro, Graziano Pesole, Sabina Tangaro, Giancarlo Logroscino and Roberto Bellotti
Genes 2022, 13(5), 727; https://doi.org/10.3390/genes13050727 - 21 Apr 2022
Cited by 16 | Viewed by 3428
Abstract
The increased incidence and the significant health burden associated with Parkinson’s disease (PD) have stimulated substantial research efforts towards the identification of effective treatments and diagnostic procedures. Despite technological advancements, a cure is still not available and PD is often diagnosed a long [...] Read more.
The increased incidence and the significant health burden associated with Parkinson’s disease (PD) have stimulated substantial research efforts towards the identification of effective treatments and diagnostic procedures. Despite technological advancements, a cure is still not available and PD is often diagnosed a long time after onset when irreversible damage has already occurred. Blood transcriptomics represents a potentially disruptive technology for the early diagnosis of PD. We used transcriptome data from the PPMI study, a large cohort study with early PD subjects and age matched controls (HC), to perform the classification of PD vs. HC in around 550 samples. Using a nested feature selection procedure based on Random Forests and XGBoost we reached an AUC of 72% and found 493 candidate genes. We further discussed the importance of the selected genes through a functional analysis based on GOs and KEGG pathways. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
Show Figures

Figure 1

12 pages, 1350 KiB  
Article
Elucidating Hexanucleotide Repeat Number and Methylation within the X-Linked Dystonia-Parkinsonism (XDP)-Related SVA Retrotransposon in TAF1 with Nanopore Sequencing
by Theresa Lüth, Joshua Laβ, Susen Schaake, Inken Wohlers, Jelena Pozojevic, Roland Dominic G. Jamora, Raymond L. Rosales, Norbert Brüggemann, Gerard Saranza, Cid Czarina E. Diesta, Kathleen Schlüter, Ronnie Tse, Charles Jourdan Reyes, Max Brand, Hauke Busch, Christine Klein, Ana Westenberger and Joanne Trinh
Genes 2022, 13(1), 126; https://doi.org/10.3390/genes13010126 - 11 Jan 2022
Cited by 10 | Viewed by 3029
Abstract
Background: X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by progressive dystonia and parkinsonism. It is caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion in the TAF1 gene with a polymorphic (CCCTCT)n domain that acts as a genetic modifier of [...] Read more.
Background: X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by progressive dystonia and parkinsonism. It is caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion in the TAF1 gene with a polymorphic (CCCTCT)n domain that acts as a genetic modifier of disease onset and expressivity. Methods: Herein, we used Nanopore sequencing to investigate SVA genetic variability and methylation. We used blood-derived DNA from 96 XDP patients for amplicon-based deep Nanopore sequencing and validated it with fragment analysis which was performed using fluorescence-based PCR. To detect methylation from blood- and brain-derived DNA, we used a Cas9-targeted approach. Results: High concordance was observed for hexanucleotide repeat numbers detected with Nanopore sequencing and fragment analysis. Within the SVA locus, there was no difference in genetic variability other than variations of the repeat motif between patients. We detected high CpG methylation frequency (MF) of the SVA and flanking regions (mean MF = 0.94, SD = ±0.12). Our preliminary results suggest only subtle differences between the XDP patient and the control in predicted enhancer sites directly flanking the SVA locus. Conclusions: Nanopore sequencing can reliably detect SVA hexanucleotide repeat numbers, methylation and, lastly, variation in the repeat motif. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
Show Figures

Figure 1

12 pages, 9803 KiB  
Article
Microarray Genotyping Identifies New Loci Associated with Dementia in Parkinson’s Disease
by Sungyang Jo, Kye Won Park, Yun Su Hwang, Seung Hyun Lee, Ho-Sung Ryu and Sun Ju Chung
Genes 2021, 12(12), 1975; https://doi.org/10.3390/genes12121975 - 10 Dec 2021
Cited by 6 | Viewed by 2316
Abstract
Dementia is one of the most disabling nonmotor symptoms of Parkinson’s disease (PD). However, the risk factors contributing to its development remain unclear. To investigate genetic variants associated with dementia in PD, we performed microarray genotyping based on a customized platform utilizing variants [...] Read more.
Dementia is one of the most disabling nonmotor symptoms of Parkinson’s disease (PD). However, the risk factors contributing to its development remain unclear. To investigate genetic variants associated with dementia in PD, we performed microarray genotyping based on a customized platform utilizing variants identified in previous genetic studies. Microarray genotyping was performed in 313 PD patients with dementia, 321 PD patients without dementia, and 635 healthy controls. The primary analysis was performed using a multiple logistic regression model adjusted for age and sex. SNCA single nucleotide polymorphism (SNP) rs11931074 was determined to be most significantly associated with PD (odds ratio = 0.66, 95% confidence interval = 0.56–0.78, p = 7.75 × 10−7). In the analysis performed for patients with PD only, MUL1 SNP rs3738128 (odds ratio = 2.52, 95% confidence interval = 1.68–3.79, p = 8.75 × 10−6) was found to be most significantly associated with dementia in PD. SNPs in ZHX2 and ERP29 were also associated with dementia in PD. This microarray genomic study identified new loci of MUL1 associated with dementia in PD, suggesting an essential role of mitochondrial dysfunction in the development of dementia in patients with PD. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
Show Figures

Figure 1

21 pages, 21464 KiB  
Article
Validity and Prognostic Value of a Polygenic Risk Score for Parkinson’s Disease
by Sebastian Koch, Björn-Hergen Laabs, Meike Kasten, Eva-Juliane Vollstedt, Jos Becktepe, Norbert Brüggemann, Andre Franke, Ulrike M. Krämer, Gregor Kuhlenbäumer, Wolfgang Lieb, Brit Mollenhauer, Miriam Neis, Claudia Trenkwalder, Eva Schäffer, Tatiana Usnich, Michael Wittig, Christine Klein, Inke R. König, Katja Lohmann, Michael Krawczak and Amke Caliebeadd Show full author list remove Hide full author list
Genes 2021, 12(12), 1859; https://doi.org/10.3390/genes12121859 - 23 Nov 2021
Cited by 16 | Viewed by 3625
Abstract
Idiopathic Parkinson’s disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the risk for a [...] Read more.
Idiopathic Parkinson’s disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the risk for a disease like PD in a single quantity. However, reassessment of the performance of a given PRS in independent data sets is a precondition for establishing the PRS as a valid tool to this end. We studied a previously proposed PRS for PD in a separate genetic data set, comprising 1914 PD cases and 4464 controls, and were able to replicate its ability to differentiate between cases and controls. We also assessed theoretically the prognostic value of the PD-PRS, i.e., its ability to predict the development of PD in later life for healthy individuals. As it turned out, the PD-PRS alone can be expected to perform poorly in this regard. Therefore, we conclude that the PD-PRS could serve as an important research tool, but that meaningful PRS-based prognosis of PD at an individual level is not feasible. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
Show Figures

Figure 1

18 pages, 3139 KiB  
Article
Comparative Transcriptome Analysis in Monocyte-Derived Macrophages of Asymptomatic GBA Mutation Carriers and Patients with GBA-Associated Parkinson’s Disease
by Tatiana Usenko, Anastasia Bezrukova, Katerina Basharova, Alexandra Panteleeva, Mikhail Nikolaev, Alena Kopytova, Irina Miliukhina, Anton Emelyanov, Ekaterina Zakharova and Sofya Pchelina
Genes 2021, 12(10), 1545; https://doi.org/10.3390/genes12101545 - 29 Sep 2021
Cited by 9 | Viewed by 2997
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)
Show Figures

Graphical abstract

13 pages, 2337 KiB  
Article
C9orf72-G4C2 Intermediate Repeats and Parkinson’s Disease; A Data-Driven Hypothesis
by Hila Kobo, Orly Goldstein, Mali Gana-Weisz, Anat Bar-Shira, Tanya Gurevich, Avner Thaler, Anat Mirelman, Nir Giladi and Avi Orr-Urtreger
Genes 2021, 12(8), 1210; https://doi.org/10.3390/genes12081210 - 5 Aug 2021
Cited by 2 | Viewed by 2192
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)
Show Figures

Figure 1

Review

Jump to: Editorial, Research

33 pages, 575 KiB  
Review
Human Induced Pluripotent Stem Cell Phenotyping and Preclinical Modeling of Familial Parkinson’s Disease
by Jeffrey Kim, Etienne W. Daadi, Thomas Oh, Elyas S. Daadi and Marcel M. Daadi
Genes 2022, 13(11), 1937; https://doi.org/10.3390/genes13111937 - 25 Oct 2022
Cited by 4 | Viewed by 2606
Abstract
Parkinson’s disease (PD) is primarily idiopathic and a highly heterogenous neurodegenerative disease with patients experiencing a wide array of motor and non-motor symptoms. A major challenge for understanding susceptibility to PD is to determine the genetic and environmental factors that influence the mechanisms [...] Read more.
Parkinson’s disease (PD) is primarily idiopathic and a highly heterogenous neurodegenerative disease with patients experiencing a wide array of motor and non-motor symptoms. A major challenge for understanding susceptibility to PD is to determine the genetic and environmental factors that influence the mechanisms underlying the variations in disease-associated traits. The pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the brain and post-mortem Lewy pathology, which leads to the loss of projecting axons innervating the striatum and to impaired motor and cognitive functions. While the cause of PD is still largely unknown, genome-wide association studies provide evidence that numerous polymorphic variants in various genes contribute to sporadic PD, and 10 to 15% of all cases are linked to some form of hereditary mutations, either autosomal dominant or recessive. Among the most common mutations observed in PD patients are in the genes LRRK2, SNCA, GBA1, PINK1, PRKN, and PARK7/DJ-1. In this review, we cover these PD-related mutations, the use of induced pluripotent stem cells as a disease in a dish model, and genetic animal models to better understand the diversity in the pathogenesis and long-term outcomes seen in PD patients. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
20 pages, 2080 KiB  
Review
Does the Expression and Epigenetics of Genes Involved in Monogenic Forms of Parkinson’s Disease Influence Sporadic Forms?
by Aymeric Lanore, Suzanne Lesage, Louise-Laure Mariani, Poornima Jayadev Menon, Philippe Ravassard, Helene Cheval, Olga Corti, Alexis Brice and Jean-Christophe Corvol
Genes 2022, 13(3), 479; https://doi.org/10.3390/genes13030479 - 8 Mar 2022
Cited by 7 | Viewed by 3799
Abstract
Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already [...] Read more.
Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involved in sporadic PD. This review will focus on the epigenetic mechanisms regulating their expression, since these are the genes for which we currently have the most information available. Despite technical challenges, epigenetic epidemiology offers new insights on revealing altered biological pathways and identifying predictive biomarkers for the onset and progression of PD. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
Show Figures

Figure 1

25 pages, 737 KiB  
Review
Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing
by Fangzhi Jia, Avi Fellner and Kishore Raj Kumar
Genes 2022, 13(3), 471; https://doi.org/10.3390/genes13030471 - 7 Mar 2022
Cited by 51 | Viewed by 10140
Abstract
Parkinson’s disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and [...] Read more.
Parkinson’s disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson’s disease genes include autosomal dominant forms (SNCA, LRRK2, and VPS35) and autosomal recessive forms (PRKN, PINK1 and DJ1). Furthermore, mutations in the GBA gene are a key risk factor for Parkinson’s disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, and SYNJ1. Furthermore, numerous genes have recently been implicated in Parkinson’s disease, such as CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C. Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson’s disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson’s disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
Show Figures

Figure 1

19 pages, 1594 KiB  
Review
Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease
by Jannik Prasuhn and Norbert Brüggemann
Genes 2021, 12(11), 1840; https://doi.org/10.3390/genes12111840 - 22 Nov 2021
Cited by 15 | Viewed by 3841
Abstract
Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a [...] Read more.
Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results: Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions: Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies. Full article
(This article belongs to the Special Issue Parkinson's Disease: Genetics and Pathogenesis)
Show Figures

Figure 1

11 pages, 784 KiB  
Review
Mapping the Diverse and Inclusive Future of Parkinson’s Disease Genetics and Its Widespread Impact
by Inas Elsayed, Alejandro Martinez-Carrasco, Mario Cornejo-Olivas and Sara Bandres-Ciga
Genes 2021, 12(11), 1681; https://doi.org/10.3390/genes12111681 - 23 Oct 2021
Cited by 5 | Viewed by 2673
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)
Show Figures

Figure 1

Back to TopTop