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Parkinson's Disease: New Molecular and Cellular Mechanistic Insights, Causality and Interventions

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 (31 December 2023) | Viewed by 4443

Special Issue Editors

Department of Biochemistry, Medical School of the Autonomous University of Madrid, Madrid, Spain
Interests: proteostasis; complex chronic diseases; causality; neurodegeneration; Parkinson’s disease
Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Avda Puerta De Hierro S/N, 28040 Madrid, Spain
Interests: proteostasis; protein synthesis; protein degradation; proteasome; neurodegeneration

Special Issue Information

Dear Colleagues, 

Parkinson’s disease (and its related synucleinopathies) is a chronic complex disease. A general characteristic shared by this disease category is that patient clinical phenotypes can be explained by inherited gene perturbations in 5–10% of cases, but most cases are sporadic. The interplay of genome and environment (including the identification of specific exposures) requires the coalition of both observational and experimental studies aiming to understand the cellular and molecular mechanisms that can eventually explain the different phenotypic levels, from mRNA and protein to patient clinical phenotype.

This Special Issue focuses on addressing a comprehensive relationship between certain molecular and cellular cues and the pathological pathways implicated in the onset and  progression of the disease. A robust body of knowledge regarding the multilevel processes involved in the maintenance of an adequate cellular homeostasis will transcend observational and experimental correlational studies and will unveil dependent and independent causal effects at a functional level, likely helping to design more successful interventions. We hope that your original or critical review contributions will become a cradle of the post-genomic aeon in Parkinson’s disease.

We would also like to take this opportunity to express our sincere thanks to Dr. Raúl Sánchez-Lanzas, as our promotion editor, who focuses on young scholars’ contributions using transversal interdisciplinary approaches in Parkinson’s disease.

Prof. Dr. José G. Castaño
Dr. Beatriz Álvarez-Castelao
Guest Editors

Manuscript Submission Information

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Keywords

  • new molecular and cellular mechanistic insights
  • spatio-temporal interplay of molecular, subcellular and cellular mechanisms
  • omics and multi-omic networks
  • spatio-temporal single cell omics
  • phenotypic determination at different complexity levels
  • genome and environment interactions
  • exposome
  • assessing causality (i.e: Bayesian networks, SEM, DAGs) in observational and experimental studies
  • proof of concept of new cellular and molecular interventions

Published Papers (2 papers)

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Review

25 pages, 1178 KiB  
Review
Beyond Strains: Molecular Diversity in Alpha-Synuclein at the Center of Disease Heterogeneity
by Marcelina J. Wojewska, Maria Otero-Jimenez, Jose Guijarro-Nuez and Javier Alegre-Abarrategui
Int. J. Mol. Sci. 2023, 24(17), 13199; https://doi.org/10.3390/ijms241713199 - 25 Aug 2023
Cited by 1 | Viewed by 1132
Abstract
Alpha-synucleinopathies (α-synucleinopathies) such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are all characterized by aggregates of alpha-synuclein (α-syn), but display heterogeneous clinical and pathological phenotypes. The mechanism underlying this heterogeneity is thought [...] Read more.
Alpha-synucleinopathies (α-synucleinopathies) such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are all characterized by aggregates of alpha-synuclein (α-syn), but display heterogeneous clinical and pathological phenotypes. The mechanism underlying this heterogeneity is thought to be due to diversity in the α-syn strains present across the diseases. α-syn obtained from the post-mortem brain of patients who lived with these conditions is heterogenous, and displays a different protease sensitivity, ultrastructure, cytotoxicity, and seeding potential. The primary aim of this review is to summarize previous studies investigating these concepts, which not only reflect the idea of different syn strains being present, but demonstrate that each property explains a small part of a much larger puzzle. Strains of α-syn appear at the center of the correlation between α-syn properties and the disease phenotype, likely influenced by external factors. There are considerable similarities in the properties of disease-specific α-syn strains, but MSA seems to consistently display more aggressive traits. Elucidating the molecular underpinnings of heterogeneity amongst α-synucleinopathies holds promise for future clinical translation, allowing for the development of personalized medicine approaches tackling the root cause of each α-synucleinopathy. Full article
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31 pages, 2032 KiB  
Review
Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview
by Vidal Yahya, Alessio Di Fonzo and Edoardo Monfrini
Int. J. Mol. Sci. 2023, 24(7), 6338; https://doi.org/10.3390/ijms24076338 - 28 Mar 2023
Cited by 2 | Viewed by 2530
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (LRRK2, VPS35, VPS13C, and ATP13A2) and synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, and DNAJC6). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., GBA1, SMPD1, TMEM175, and SCARB2) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall “lysosomal genetic burden”, namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD. Full article
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