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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 January 2023) | Viewed by 12527

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Prof. Dr. Eng King Tan

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Guest Editor

Duke-NUS Medical School, Singapore 169857, Singapore
Interests: genetics of PD and related disorders; experimental and clinical therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

Parkinson's disease is a type of neurodegenerative disease that causes shaking and stiffness, as well as difficulty with walking, balance, and coordination. The symptoms of this disease usually appear gradually and worsen over time. In recent years, some progress has been made in the study of Parkinson's disease.

In this Special Issue, we aim to include original and review articles that focus on the dietary, lifestyle and genetic risk factors of Parkinson’s disease (PD), as well as expert opinions and discussions on the changing research landscape, methodologies and challenges related to the etiology and epidemiology of PD.

The state-of-the-art articles will also include original research or reviews on novel mechanistic insights based on animal models and experimental therapeutics (including gene therapies), animal and human studies on neurostimulation and neuromodulation approaches, clinical drug and cellular replacement trials, and imaging and digitalization studies.

Finally, we encourage submissions pertaining to the future directions of PD research, in particular, on the application of modern technology (at both the cell and body level) for diagnostic and therapeutic purposes.

Prof. Dr. Eng King Tan
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
animal models
gene therapies
dietary

Published Papers (6 papers)

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Research

21 pages, 2832 KiB

Open AccessArticle

Enhanced IRE1α Phosphorylation/Oligomerization-Triggered XBP1 Splicing Contributes to Parkin-Mediated Prevention of SH-SY5Y Cell Death under Nitrosative Stress

by Tsung-Lang Chiu, Hsin-Yi Huang, Hui-Fen Chang, Hsin-Rong Wu and Mei-Jen Wang

Int. J. Mol. Sci. 2023, 24(3), 2017; https://doi.org/10.3390/ijms24032017 - 19 Jan 2023

Viewed by 1550

Abstract

Mutations in parkin, a neuroprotective protein, are the predominant cause of autosomal recessive juvenile Parkinson’s disease. Neuroinflammation-derived nitrosative stress has been implicated in the etiology of the chronic neurodegeneration. However, the interactions between genetic predisposition and nitrosative stress contributing to the degeneration of dopaminergic (DA) neurons remain incompletely understood. Here, we used the SH-SY5Y neuroblastoma cells to investigate the function of parkin and its pathogenic mutants in relation to cell survival under nitric oxide (NO) exposure. The results showed that overexpression of wild-type parkin protected SH-SY5Y cells from NO-induced apoptosis in a reactive oxygen species-dependent manner. Under nitrosative stress conditions, parkin selectively upregulated the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) signaling axis, an unfolded protein response signal through the sensor IRE1α, which controls the splicing of XBP1 mRNA. Inhibition of XBP1 mRNA splicing either by pharmacologically inhibiting IRE1α endoribonuclease activity or by genetically knocking down XBP1 interfered with the protective activity of parkin. Furthermore, pathogenic parkin mutants with a defective protective capacity showed a lower ability to activate the IRE1α/XBP1 signaling. Finally, we demonstrated that IRE1α activity augmented by parkin was possibly mediated through interacting with IRE1α to regulate its phosphorylation/oligomerization processes, whereas mutant parkin diminished its binding to and activation of IRE1α. Thus, these results support a direct link between the protective activity of parkin and the IRE1α/XBP1 pathway in response to nitrosative stress, and mutant parkin disrupts this function. Full article

(This article belongs to the Special Issue Molecular Research on Parkinson's Disease)

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18 pages, 2873 KiB

Open AccessArticle

Glial Cultures Differentiated from iPSCs of Patients with PARK2-Associated Parkinson’s Disease Demonstrate a Pro-Inflammatory Shift and Reduced Response to TNFα Stimulation

by Tatiana Gerasimova, Ekaterina Stepanenko, Lyudmila Novosadova, Elena Arsenyeva, Darya Shimchenko, Vyacheslav Tarantul, Igor Grivennikov, Valentina Nenasheva and Ekaterina Novosadova

Int. J. Mol. Sci. 2023, 24(3), 2000; https://doi.org/10.3390/ijms24032000 - 19 Jan 2023

Cited by 2 | Viewed by 1701

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative diseases characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra. Mutations in the PARK2 gene are a frequent cause of familial forms of PD. Sustained chronic neuroinflammation in the central nervous system makes a significant contribution to neurodegeneration events. In response to inflammatory factors produced by activated microglia, astrocytes change their transcriptional programs and secretion profiles, thus acting as immunocompetent cells. Here, we investigated iPSC-derived glial cell cultures obtained from healthy donors (HD) and from PD patients with PARK2 mutations in resting state and upon stimulation by TNFα. The non-stimulated glia of PD patients demonstrated higher IL1B and IL6 expression levels and increased IL6 protein synthesis, while BDNF and GDNF expression was down-regulated when compared to that of the glial cells of HDs. In the presence of TNFα, all of the glial cultures displayed a multiplied expression of genes encoding inflammatory cytokines: TNFA, IL1B, and IL6, as well as IL6 protein synthesis, although PD glia responded to TNFα stimulation less strongly than HD glia. Our results demonstrated a pro-inflammatory shift, a suppression of the neuroprotective gene program, and some depletion of reactivity to TNFα in PARK2-deficient glia compared to glial cells of HDs. Full article

(This article belongs to the Special Issue Molecular Research on Parkinson's Disease)

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14 pages, 5920 KiB

Open AccessArticle

Spatial Transcriptome Profiling of Mouse Hippocampal Single Cell Microzone in Parkinson’s Disease

by Erteng Jia, Yuqi Sheng, Huajuan Shi, Ying Wang, Ying Zhou, Zhiyu Liu, Ting Qi, Min Pan, Yunfei Bai, Xiangwei Zhao and Qinyu Ge

Int. J. Mol. Sci. 2023, 24(3), 1810; https://doi.org/10.3390/ijms24031810 - 17 Jan 2023

Cited by 4 | Viewed by 2648

Abstract

The hippocampus is an important part of the limbic system in the human brain that has essential roles in spatial navigation and cognitive functions. It is still unknown how gene expression changes in single-cell in different spatial locations of the hippocampus of Parkinson’s disease. The purpose of this study was to analyze the gene expression features of single cells in different spatial locations of mouse hippocampus, and to explore the effects of gene expression regulation on learning and memory mechanisms. Here, we obtained 74 single-cell samples from different spatial locations in a mouse hippocampus through microdissection technology, and used single-cell RNA-sequencing and spatial transcriptome sequencing to visualize and quantify the single-cell transcriptome features of tissue sections. The results of differential expression analysis showed that the expression of Sv2b, Neurod6, Grp and Stk32b genes in a hippocampus single cell at different locations was significantly different, and the marker genes of CA1, CA3 and DG subregions were identified. The results of gene function enrichment analysis showed that the up-regulated differentially expressed genes Tubb2a, Eno1, Atp2b1, Plk2, Map4, Pex5l, Fibcd1 and Pdzd2 were mainly involved in neuron to neuron synapse, vesicle-mediated transport in synapse, calcium signaling pathway and neurodegenerative disease pathways, thus affecting learning and memory function. It revealed the transcriptome profile and heterogeneity of spatially located cells in the hippocampus of PD for the first time, and demonstrated that the impaired learning and memory ability of PD was affected by the synergistic effect of CA1 and CA3 subregions neuron genes. These results are crucial for understanding the pathological mechanism of the Parkinson’s disease and making precise treatment plans. Full article

(This article belongs to the Special Issue Molecular Research on Parkinson's Disease)

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20 pages, 5860 KiB

Open AccessArticle

Role and Dysregulation of miRNA in Patients with Parkinson’s Disease

by Michele Salemi, Giovanna Marchese, Giuseppe Lanza, Filomena I. I. Cosentino, Maria Grazia Salluzzo, Francesca A. Schillaci, Giovanna Maria Ventola, Angela Cordella, Maria Ravo and Raffaele Ferri

Int. J. Mol. Sci. 2023, 24(1), 712; https://doi.org/10.3390/ijms24010712 - 31 Dec 2022

Cited by 8 | Viewed by 2379

Abstract

Parkinson’s disease (PD) is a neurodegenerative synucleinopathy that has a not yet fully understood molecular pathomechanism behind it. The role of risk genes regulated by small non-coding RNAs, or microRNAs (miRNAs), has also been highlighted in PD, where they may influence disease progression and comorbidities. In this case-control study, we analyzed miRNAs on peripheral blood mononuclear cells by means of RNA-seq in 30 participants, with the aim of identifying miRNAs differentially expressed in PD compared to age-matched healthy controls. Additionally, we investigated the pathways influenced by differentially expressed miRNAs and assessed whether a specific pathway could potentially be associated with PD susceptibility (enrichment analyses performed using the Ingenuity Pathway Analysis tools). Overall, considering that the upregulation of miRNAs might be related with the downregulation of their messenger RNA targets, and vice versa, we found several putative targets of dysregulated miRNAs (i.e., upregulated: hsa-miR-1275, hsa-miR-23a-5p, hsa-miR-432-5p, hsa-miR-4433b-3p, and hsa-miR-4443; downregulated: hsa-miR-142-5p, hsa-miR-143-3p, hsa-miR-374a-3p, hsa-miR-542-3p, and hsa-miR-99a-5p). An inverse connection between cancer and neurodegeneration, called “inverse comorbidity”, has also been noted, showing that some genes or miRNAs may be expressed oppositely in neurodegenerative disorders and in some cancers. Therefore, it may be reasonable to consider these miRNAs as potential diagnostic markers and outcome measures. Full article

(This article belongs to the Special Issue Molecular Research on Parkinson's Disease)

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12 pages, 300 KiB

Open AccessCommunication

Genetic Study of Early Onset Parkinson’s Disease in Cyprus

by Rana Abu Manneh, Paraskevi P. Chairta, Ellie Mitsi, Maria A. Loizidou, Andrea N. Georgiou, Yiolanda P. Christou, Marios Pantzaris, Eleni Zamba-Papanicolaou and Andreas Hadjisavvas

Int. J. Mol. Sci. 2022, 23(23), 15369; https://doi.org/10.3390/ijms232315369 - 6 Dec 2022

Cited by 1 | Viewed by 2130

Abstract

Parkinson’s Disease (PD) is a multifactorial neurodegenerative disease characterized by motor and non-motor symptoms. The etiology of PD remains unclear. However, several studies have demonstrated the interplay of genetic, epigenetic, and environmental factors in PD. Early-onset PD (EOPD) is a subgroup of PD diagnosed between the ages of 21 and 50. Population genetic studies have demonstrated great genetic variability amongst EOPD patients. Hence, this study aimed to obtain a genetic landscape of EOPD in the Cypriot population. Greek-Cypriot EOPD patients (n = 48) were screened for variants in the six most common EOPD-associated genes (PINK1, PRKN, FBXO7, SNCA, PLA2G6, and DJ-1). This included DNA sequencing and Multiplex ligation-dependent probe amplification (MLPA). One previously described frameshift variant in PINK1 (NM_032409.3:c.889del) was detected in five patients (10.4%)—the largest number to be detected to date. Copy number variations in the PRKN gene were identified in one homozygous and 3 compound heterozygous patients (8.3%). To date, the pathogenic variants identified in this study have explained the PD phenotype for 18.8% of the EOPD cases. The results of this study may contribute to the genetic screening of EOPD in Cyprus. Full article

(This article belongs to the Special Issue Molecular Research on Parkinson's Disease)

17 pages, 2257 KiB

Open AccessArticle

Rhus Coriaria L. Extract: Antioxidant Effect and Modulation of Bioenergetic Capacity in Fibroblasts from Parkinson’s Disease Patients and THP-1 Macrophages

by Camilla Isgrò, Ludovica Spagnuolo, Elisa Pannucci, Luigi Mondello, Luca Santi, Laura Dugo and Anna Maria Sardanelli

Int. J. Mol. Sci. 2022, 23(21), 12774; https://doi.org/10.3390/ijms232112774 - 23 Oct 2022

Cited by 4 | Viewed by 1499

Abstract

Sumac, Rhus coriaria L., is a Mediterranean plant showing several useful properties, such as antioxidant and neuroprotective effects. Currently, there is no evidence about its possible neuroprotective action in Parkinson’s disease (PD). We hypothesized that sumac could modulate mitochondrial functionality in fibroblasts of familial early-onset PD patients showing PARK2 mutations. Sumac extract volatile profile, polyphenolic content and antioxidant activity have been previously characterized. We evaluated ROS and ATP levels on sumac-treated patients’ and healthy control fibroblasts. In PD fibroblasts, all treatments were effective in reducing H₂O₂ levels, while patients’ ATP content was modulated differently, probably due to the varying mutations in the PARK2 gene found in individual patients which are also involved in different mitochondrial phenotypes. We also investigated the effect of sumac extract on THP-1-differentiated macrophages, which show different embryogenic origin with respect to fibroblasts. In THP-1 macrophages, sumac treatment determined a reduction in H₂O₂ levels and an increase in the mitochondrial ATP content in M1, assuming that sumac could polarize the M1 to M2 phenotype, as demonstrated with other food-derived compounds rich in polyphenols. In conclusion, Rhus coriaria L. extracts could represent a potential nutraceutical approach to PD. Full article

(This article belongs to the Special Issue Molecular Research on Parkinson's Disease)

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