Role of Alpha-Synuclein in Neurodegenerative Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: 31 August 2026 | Viewed by 4571

Special Issue Editor


E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
Interests: toll like receptors in neurodegenerations; toll like receptor 4 in Parkinson’s disease; neuroinflammation; alpha synuclein accumulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The proteostasis network ensures the delicate balance among protein synthesis, folding, and degradation. It encompasses mechanisms such as the ubiquitin–proteasome system, autophagy, molecular chaperones, and heat shock proteins. Collectively, these pathways regulate both the quantity and quality of cellular proteins and facilitate their removal when necessary. ​

Disruptions in proteostasis have been linked to the development of synucleinopathies, a class of neurodegenerative diseases characterized by the abnormal accumulation of α-synuclein (αSyn) aggregates within neurons and various non-neuronal cells, including microglia, pericytes, astrocytes, and oligodendrocytes. The precise mechanisms underlying αSyn misfolding remain inadequately understood, though it is believed to result from a combination of environmental exposures and genetic predispositions.

This Special Issue aims to offer a comprehensive overview of synucleinopathies, encompassing the molecular mechanisms that govern synuclein dysfunction, including b- and g-synuclein. Special emphasis will be placed on inflammatory pathways, authophagy dysfunctions, and synuclein spreading along with new sensitive assays to detect very low levels of abnormal structured protofibrils in various biological fluids facilitating early diagnosis even before clinical symptoms emerge.

Dr. Carmela Conte
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 250 words) can be sent to the Editorial Office for assessment.

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. Cells is an international peer-reviewed open access semimonthly 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 2700 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

  • Alpha-, Beta-, and Gamma-synuclein
  • synucleinopathies
  • neurodegeneration
  • neuroinflammation
  • authophagy
  • Parkinson's disease
  • non-motor symptoms
  • Alzheimer's disease
  • multiple system atrophy
  • psychiatric diseases

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (3 papers)

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

Research

Jump to: Review

24 pages, 2696 KB  
Article
Proteomics of Patient-Derived Striatal Medium Spiny Neurons in Multiple System Atrophy
by Nadine J. Smandzich, Andreas Pich, Thomas Gschwendtberger, Stephan Greten, Lan Ye, Martin Klietz, Alessio Di Fonzo, Lisa M. Henkel and Florian Wegner
Cells 2025, 14(17), 1394; https://doi.org/10.3390/cells14171394 - 6 Sep 2025
Cited by 3 | Viewed by 1826
Abstract
The rare and rapidly progressive neurodegenerative disease multiple system atrophy (MSA) mainly affects the striatum and other subcortical brain regions. In this atypical Parkinsonian syndrome, the protein alpha-synuclein aggregates and misfolds in neurons as well as glial cells and is released in elevated [...] Read more.
The rare and rapidly progressive neurodegenerative disease multiple system atrophy (MSA) mainly affects the striatum and other subcortical brain regions. In this atypical Parkinsonian syndrome, the protein alpha-synuclein aggregates and misfolds in neurons as well as glial cells and is released in elevated amounts by hypoexcitable neurons. Mitochondrial dysregulation affects the biosynthesis of coenzyme Q10 and the activity of the respiratory chain, as shown in an induced pluripotent stem cell (iPSC) model. Proteome studies of cerebrospinal fluid and brain tissue from MSA patients yielded inconsistent results regarding possible protein changes due to small and combined groups of atypical Parkinsonian syndromes. In this study, we analysed the cellular proteome of MSA patient-derived striatal GABAergic medium spiny neurons. We observed 25 significantly upregulated and 16 significantly downregulated proteins in MSA cell lines compared to matched healthy controls. Various protein types involved in diverse molecular functions and cellular processes emphasise the multifaceted pathomechanisms of MSA. These data could contribute to the development of novel disease-modifying treatment strategies for MSA patients. Full article
(This article belongs to the Special Issue Role of Alpha-Synuclein in Neurodegenerative Diseases)
Show Figures

Figure 1

Review

Jump to: Research

13 pages, 602 KB  
Review
Role of Alpha-Synuclein in Frontotemporal Dementia: Narrative Review
by Anastasia Bougea
Cells 2026, 15(5), 470; https://doi.org/10.3390/cells15050470 - 5 Mar 2026
Viewed by 646
Abstract
Background: Frontotemporal dementia (FTD) is traditionally classified based on the accumulation of either tau or TDP-43 proteins; however, the presence of alpha-synuclein (α-Syn) in these patients is increasingly recognized as a critical factor driving disease progression. Methods: A comprehensive narrative review of recent [...] Read more.
Background: Frontotemporal dementia (FTD) is traditionally classified based on the accumulation of either tau or TDP-43 proteins; however, the presence of alpha-synuclein (α-Syn) in these patients is increasingly recognized as a critical factor driving disease progression. Methods: A comprehensive narrative review of recent clinical, neuropathological, and biochemical studies was conducted, focusing on cases of FTLD-synuclein and the occurrence of alpha-syn as a co-pathology in more common FTD variants. Results: Current evidence indicates that α-syn often co-aggregates with tau and TDP-43 via “cross-seeding” mechanisms, significantly accelerating neuronal loss and contributing to clinical heterogeneity. Although FTLD-synuclein is a rare, distinct subtype that mimics atypical multiple system atrophy, secondary α-syn pathology is common and strongly correlates with rapid cognitive decline. Furthermore, existing diagnostic biomarkers typically fail to detect this pathological overlap, which may explain the limited efficacy in protein-specific clinical trials. Conclusions: α-Syn is a major, yet under-recognized, catalyst of neurodegeneration within the FTD spectrum. The findings emphasize the need for future therapeutic and diagnostic strategies to adopt multi-target approaches, addressing the synergistic toxicity of multiple protein aggregates rather than isolating single protein in isolation. Full article
(This article belongs to the Special Issue Role of Alpha-Synuclein in Neurodegenerative Diseases)
Show Figures

Figure 1

30 pages, 2440 KB  
Review
Alpha-Synuclein in Neurodegeneration: From Shared Biology to Disease-Specific Phenotypes
by Feifei Su, Woojin S. Kim, Glenda M. Halliday and YuHong Fu
Cells 2026, 15(5), 451; https://doi.org/10.3390/cells15050451 - 3 Mar 2026
Viewed by 1493
Abstract
Alpha-synuclein (αSyn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we suggest that αSyn-driven disease emerges within specific neural circuits through the combined [...] Read more.
Alpha-synuclein (αSyn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we suggest that αSyn-driven disease emerges within specific neural circuits through the combined effects of cell-type-specific roles, subcellular environments, post-translational modifications (PTMs), and co-pathology. These interacting and additive dimensions, rather than αSyn alone, generate the pathological diversity, shaping whether pathology manifests as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or mixed dementia phenotypes. We integrate recent advances on the physiological roles of αSyn in neurons and glia (astrocytes, oligodendrocytes, and microglia), its compartment-dependent (e.g., synaptic and nuclear) functions, and the molecular transitions (e.g., mediated by pS129) that convert functional assemblies into pathogenic conformers. Building on this foundation, we outline mechanisms through which these factors contribute to disease-specific vulnerability, progression, and clinical heterogeneity. Finally, we highlight how this multidimensional perspective on αSyn biology can inform the development of next-generation biomarkers that support precision therapies across distinct disorders. Full article
(This article belongs to the Special Issue Role of Alpha-Synuclein in Neurodegenerative Diseases)
Show Figures

Figure 1

Back to TopTop