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New Challenges of Parkinson’s Disease, 2nd Edition

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: 20 September 2026 | Viewed by 6069

Special Issue Editors

Dr. Franca Rosa Guerini

E-Mail Website
Guest Editor
Laboratory of Molecular Medicine and Biotechnology, IRCCS Fondazione Don Carlo Gnocchi, Via Capecelatro 66, 20148 Milan, Italy
Interests: genetics; autism; neurodegenerative disorders; Alzheimer; multiple sclerosis
Special Issues, Collections and Topics in MDPI journals
Dr. Cristina Agliardi

E-Mail Website
Guest Editor
Don C. Gnocchi Foundation, IRCCS, Piazza Morandi, 3, 20121 Milano, Italy
Interests: extracellular vesicles; neurodegenerative disorders; molecular genetics; Alzheimer; multiple sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will be supervised by Dr. Cristina Agliardi and Dr. Franca R. Guerini, assisted by our Topical Advisory Panel Member Dr. Peter Antony Barbuti.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder characterized by both motor and non-motor symptoms including sleep and mood disorders and cognitive, sensory and autonomic dysfunctions. The etiology of the disease in most patients is unknown, but different genetic causes have been identified. Moreover, the existing treatments are limited in effect and mainly address the symptoms rather than the cause or the progressive course. Improving our understanding of what causes the complexity and diversity of PD is a major challenge for researchers. Tools are needed to group people with similar types of PD so that individuals who are most likely to benefit from clinical trials can be studied and their responses to treatment can be compared in a meaningful way. The aim of this Special Issue is to collect the latest research on PD in terms of:

  • Etiology understanding: genetic and environmental influences, mitochondrial dysfunction, protein aggregation, misfolding and cell-to-cell spreading mechanisms, neuroinflammation, etc.;
  • New biomarkers discovery: imaging scans (MRI, CT), extracellular vesicles in biofluids, genetics, epigenetics and microbiome analysis;
  • Novel disease-modifying treatments: gene therapy, deep brain stimulation and animal models;
  • Strategies that provide symptoms relief: diet, exercise, rehabilitation and stress reduction.

We welcome both original research and review articles.

Dr. Franca Rosa Rosa Guerini
Dr. Cristina Agliardi
Guest Editors

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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.

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Keywords

  • Parkinson’s disease
  • neurodegeneration
  • synuclein
  • diagnosis
  • genetics
  • epigenetics
  • extracellular vesicles
  • biomarkers
  • treatments
  • rehabilitation

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Published Papers (5 papers)

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Research

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23 pages, 6756 KB  
Article
Preservation of Extracellular and Tissue Dopamine During Tyrosine Hydroxylase Loss in Rat 6-OHDA Parkinson’s Model: Selective Compensation Restricted to Substantia Nigra
by Ashley Galfano, Robert McManus, Walter Navarrete, Sampada Chaudhari, Christopher Bishop and Michael F. Salvatore
Int. J. Mol. Sci. 2026, 27(9), 3923; https://doi.org/10.3390/ijms27093923 - 28 Apr 2026
Viewed by 978
Abstract
Compensatory mechanisms are thought to maintain sufficient dopamine (DA) signaling to mitigate locomotor impairment during progressive nigrostriatal neuron loss in Parkinson’s disease (PD). Recent evidence indicated augmented DA tissue content in the substantia nigra (SN), not striatum, compensates for tyrosine hydroxylase (TH) and [...] Read more.
Compensatory mechanisms are thought to maintain sufficient dopamine (DA) signaling to mitigate locomotor impairment during progressive nigrostriatal neuron loss in Parkinson’s disease (PD). Recent evidence indicated augmented DA tissue content in the substantia nigra (SN), not striatum, compensates for tyrosine hydroxylase (TH) and neuronal loss, and alleviates the severity of hypokinesia during neuronal loss. Here, we determined if increased extracellular DA in the SN may also be a compensatory mechanism to augment DA signaling. Following unilateral 6-hydroxydopamine (6-OHDA) lesion or sham-operation, we contemporaneously evaluated extracellular DA against both DA tissue and TH levels in striatum and SN at 7 and 28 days. At 7 days post-lesion, TH loss exceeded ~90% in striatum, and ~70% in the SN. The severity of DA tissue loss coincided with TH protein loss only in striatum (>90%) on both days after lesion, whereas in the SN, DA loss was absent on day 7 and significantly less than TH loss by day 28. Whereas there was a robust increase in extracellular DA in striatum in our sham-operation group, the severe TH and DA tissue loss in striatum practically abolished KCl (K+)-stimulated extracellular DA by day 7. In contrast, whereas striatal K+-stimulation had no effect on extracellular DA in the SN in sham-operation group, extracellular DA levels increased in the SN 7 days after nigrostriatal lesion: an increase no longer apparent by day 28. Thus, despite significant loss of TH protein loss in the SN, extracellular and tissue DA tissue levels were augmented during neuronal loss. These results build upon evidence that compensatory mechanisms to augment DA signaling are not engaged in striatum, and point to the SN as the locus of augmented DA signaling to offset loss of TH during nigrostriatal neuron loss. Full article
(This article belongs to the Special Issue New Challenges of Parkinson’s Disease, 2nd Edition)
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17 pages, 1741 KB  
Article
The Impact of Motor Symptom Asymmetry on the Relationship Between Non-Motor Manifestations and Neurometabolic Profiles in Parkinson’s Disease
by Lilla Bonanno, Giulia Marafioti, Alessia Biondo, Amelia Brigandì, Fabrizia Caminiti, Rosa Morabito, Angelo Quartarone, Chiara Sorbera, Rosaria Torre and Rosella Ciurleo
Int. J. Mol. Sci. 2026, 27(5), 2120; https://doi.org/10.3390/ijms27052120 - 25 Feb 2026
Viewed by 414
Abstract
Parkinson’s disease (PD) is characterized by asymmetric motor symptoms (MSs), which may influence non-motor symptoms (NMSs). This study investigated the relationship between NMSs and the neurometabolic profile of the substantia nigra (SN) and globus pallidus (GP) of patients with PD, examining how these [...] Read more.
Parkinson’s disease (PD) is characterized by asymmetric motor symptoms (MSs), which may influence non-motor symptoms (NMSs). This study investigated the relationship between NMSs and the neurometabolic profile of the substantia nigra (SN) and globus pallidus (GP) of patients with PD, examining how these associations vary according to MS asymmetry. Forty-three PD patients (20 with right-predominant motor symptoms—RPD, and 23 with left-predominant motor symptoms—LPD) and 20 healthy controls (HCs) underwent single-voxel proton magnetic resonance spectroscopy, along with comprehensive clinical assessments of MSs and NMSs. Compared with HCs, PD patients showed higher N-acetylaspartate (NAA) levels in the SN, lower myo-inositol (Ins) levels in both sides of the SN, and higher glutamate/glutamine (Glx) levels in the right GP. Choline (Cho) in the left GP was positively associated with cognitive performance. In LPD patients, compared with HCs, NAA levels were increased in the right SN, whereas Ins levels were reduced in both hemispheres. These patients reported higher anxiety and exhibited marked hemispheric asymmetry of SN NAA. In this group, higher NAA levels in the right SN were associated with fewer sleep disturbances, while Ins in the right GP was related to both cognitive function and NMS severity. RPD patients showed elevated Glx levels in the right GP compared with HCs, with no significant hemispheric differences in metabolite levels. Nevertheless, Cho in the right SN was positively associated with sleep disturbances. Overall, these findings suggest that motor asymmetry in PD influences the neurometabolic correlates of NMSs, revealing distinct metabolic-clinical profiles in RPD and LPD patients. Full article
(This article belongs to the Special Issue New Challenges of Parkinson’s Disease, 2nd Edition)
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27 pages, 6094 KB  
Article
p.N370S GBA1 Mutation Influences the Morphology and Lipid Composition of Extracellular Vesicles in Blood Plasma from Patients with Parkinson’s Disease
by Tatiana S. Usenko, Alena E. Kopytova, Artem D. Izyumchenko, Darya G. Kulabukhova, Artemiy S. Silantyev, Victoria D. Kazakova, Katerina S. Basharova, Anastasia I. Bezrukova, Luiza A. Garaeva, Evgeny B. Pichkur, Alexandra V. Artynyuk, Irina V. Miliukhina, Alla A. Timofeeva, Valentina V. Miroshnikova, Stanislav N. Naryzhny, Anton K. Emelyanov, Natalya B. Zakharzhevskaya, Andrey L. Konevega, Tatiana A. Shtam and Sofya N. Pchelina
Int. J. Mol. Sci. 2025, 26(18), 9152; https://doi.org/10.3390/ijms26189152 - 19 Sep 2025
Cited by 2 | Viewed by 1550
Abstract
Parkinson’s disease, associated with mutations in the GBA1 gene (GBA1-PD), is the most common genetic form of Parkinson’s disease (PD), marked by clinical heterogeneity influenced by mutation type. Extracellular vesicles (EVs), key mediators of intercellular communication, are implicated in PD pathogenesis through the [...] Read more.
Parkinson’s disease, associated with mutations in the GBA1 gene (GBA1-PD), is the most common genetic form of Parkinson’s disease (PD), marked by clinical heterogeneity influenced by mutation type. Extracellular vesicles (EVs), key mediators of intercellular communication, are implicated in PD pathogenesis through the transport of pathological proteins and lipids. In this study, we analyzed blood plasma-derived EVs from GBA1-PD patients carrying p.N370S and p.L444P mutations and from healthy controls using cryo-electron microscopy, lipidomics, and proteomics. EVs from GBA1-PD patients were significantly larger than those from controls, with the largest size and most multilayered vesicles observed in p.N370S carriers. Lipidomic profiling identified 237 lipid species; of these, 186 lipids were altered in p.N370S and 24 in p.L444P versus controls. Mutation carriers showed distinct lipid signatures, with p.L444P samples enriched predominantly in sphingolipids, while p.N370S carriers exhibited more extensive lipid remodeling across multiple classes, including triglycerides, cholesteryl esters, and phospholipids. Notably, Cer 23:0 was elevated across all GBA1-PD groups. Proteomic analysis revealed enrichment in pathways related to lipid transport, immune regulation, and vesicle-mediated processes. Overall, GBA1-PD patients share a distinct lipidomic EV signature, with mutation-specific patterns reflecting differing mechanisms of lysosomal dysfunction. These findings support the potential of EV profiling to unravel disease heterogeneity and identify biomarkers. Full article
(This article belongs to the Special Issue New Challenges of Parkinson’s Disease, 2nd Edition)
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Review

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24 pages, 626 KB  
Review
Copper Dyshomeostasis Affects α-Synuclein Clearance Mechanisms in Parkinson’s Disease: Insights from In Vitro Models and Translational Evidence
by Debora Musarò, Marco Greco, Martina Lanza, Marina Damato and Michele Maffia
Int. J. Mol. Sci. 2026, 27(7), 2993; https://doi.org/10.3390/ijms27072993 - 25 Mar 2026
Viewed by 621
Abstract
Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons and the accumulation of α-synuclein-rich inclusions, largely resulting from impaired protein clearance mechanisms. Copper is an essential redox-active metal in the central nervous system (CNS), but alterations in its homeostasis can [...] Read more.
Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons and the accumulation of α-synuclein-rich inclusions, largely resulting from impaired protein clearance mechanisms. Copper is an essential redox-active metal in the central nervous system (CNS), but alterations in its homeostasis can promote oxidative stress, mitochondrial dysfunction, and proteostatic failure. In vitro studies indicate that copper can promote α-synuclein misfolding, enhance oxidative stress, and interfere with both the ubiquitin–proteasome system (UPS) and the autophagy–lysosome pathway (ALP). In this review, we critically evaluate mechanistic evidence from cellular models, integrating available animal and clinical data to assess the biological significance of copper-mediated impairment of α-synuclein clearance. We highlight the current research, identify methodological limitations, and discuss whether copper imbalance acts as a primary pathogenic trigger or as a disease-modifying amplifier of proteostatic failure. Furthermore, we consider the translational implications of selectively modulating intracellular copper pools as a therapeutic strategy in PD. Finally, we will highlight unresolved issues, methodological limitations, and emerging targeted therapeutic prospects. Full article
(This article belongs to the Special Issue New Challenges of Parkinson’s Disease, 2nd Edition)
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24 pages, 697 KB  
Review
GLP-1 Signalling as a Therapeutic Avenue in Parkinson’s Disease: A Comprehensive Review
by María Paz Orozco, Valentina Vintimilla Rivadeneira and Jose E. Leon-Rojas
Int. J. Mol. Sci. 2025, 26(24), 12163; https://doi.org/10.3390/ijms262412163 - 18 Dec 2025
Cited by 1 | Viewed by 2027
Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like [...] Read more.
Parkinson’s disease (PD) is a complex neurodegenerative disorder characterised by progressive motor and non-motor impairment, in which current therapies remain symptomatic and fail to halt dopaminergic neuron loss. Growing evidence linking metabolic dysfunction, type 2 diabetes, and neurodegeneration has renewed interest in glucagon-like peptide 1 (GLP-1) receptor agonists as potential disease-modifying agents. While several recent reviews have explored the role of incretin-based therapies, the present work provides an integrative perspective by combining a mechanistic analysis of GLP-1 signalling pathways with a model-specific synthesis of preclinical findings and an appraisal of clinical translational relevance. We consolidate evidence across PI3K/Akt, MAPK/ERK, cAMP/PKA–CREB, and AMPK pathways, emphasising their convergence on mitochondrial homeostasis, proteostasis, neuroinflammation, and synaptic resilience. To enhance translational clarity, we summarise preclinical studies across major PD models, evaluate dose comparability and blood–brain barrier penetration, and identify pharmacokinetic and mechanistic factors that may explain divergent clinical outcomes. We also compare the therapeutic potential of key GLP-1 agonists, including exendin-4, liraglutide, semaglutide, lixisenatide, and emerging dual agonists. By integrating biochemical, preclinical, and clinical domains, this review provides a comprehensive framework for interpreting the current evidence and guiding the future development of incretin-based neuroprotective strategies in PD. Full article
(This article belongs to the Special Issue New Challenges of Parkinson’s Disease, 2nd Edition)
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