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Cells
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Molecular and Cellular Drivers of Parkinson's Disease
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Molecular and Cellular Drivers of Parkinson's Disease

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

Deadline for manuscript submissions: 30 September 2026 | Viewed by 1928

Special Issue Editors

Dr. Fatema Currim

E-Mail Website
Guest Editor
Hall for Discovery and Learning Research, Purdue University, 3rd Floor, RM303, S. Martin Jischke Dr., West Lafayette, IN 47907, USA
Interests: neurotoxicology; Parkinson's disease; exosomal mirnas; neurodegeneration; mitochondria; cell death and apoptosis
Prof. Dr. Jason Cannon

E-Mail Website
Guest Editor
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
Interests: neurobiology of disease; neurodegeneration; neurotoxicology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway and the abnormal and toxic aggregation of α-synuclein. Disease progression is driven by mitochondrial dysfunction, impaired proteostasis, neuroinflammation, oxidative stress, and impaired synaptic function. The complex etiology of PD is linked to an interplay between genetic predisposition and environmental exposures, yet the precise molecular and cellular mechanisms remain elusive.

This Special Issue will showcase studies that advance our understanding of these pathways and how they are regulated under PD conditions. Topics of interest include molecular signaling cascades, cell-to-cell communication, neuroimmune responses, protein aggregation dynamics, and neuroprotective strategies. This Special Issue will also explore how environmental factors influence PD-related molecular mechanisms along with the genetic predisposition of the individual. Contributions should focus on unraveling the pathophysiology of PD, exploring the mechanisms driving neurodegeneration, and identifying potential targets to combat disease progression.

Dr. Fatema Currim
Prof. Dr. Jason Cannon
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 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

  • Parkinson’s disease
  • neurodegeneration
  • mitochondrial dysfunction
  • α-synuclein aggregation
  • neurotoxicity
  • neuroinflammation
  • oxidative stress
  • environmental factors
  • gene–environment interactions
  • cell death

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Published Papers (2 papers)

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37 pages, 15160 KB  
Article
Membrane Dysfunction as a Central Mechanism in LRRK2-Associated Parkinson’s Disease: Comparative Analysis of G2019S and I1371V Variants
by Khushboo Singh, Roon Banerjee, Chandrakanta Potdar, Anisha Shaw, Rakshith Rakshith, Nitish Kamble, Vikram Holla, Ravi Yadav, Pramod Kumar Pal and Indrani Datta
Cells 2026, 15(4), 342; https://doi.org/10.3390/cells15040342 - 13 Feb 2026
Cited by 1 | Viewed by 1097
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are among the most common genetic causes of Parkinson’s disease (PD), yet substantial heterogeneity exists among pathogenic variants. How mutations in distinct functional domains of LRRK2 differentially perturb cellular homeostasis remains incompletely understood. Here, we compared [...] Read more.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are among the most common genetic causes of Parkinson’s disease (PD), yet substantial heterogeneity exists among pathogenic variants. How mutations in distinct functional domains of LRRK2 differentially perturb cellular homeostasis remains incompletely understood. Here, we compared two pathogenic LRRK2 mutations—G2019S in the kinase domain and I1371V in the GTPase domain—across multiple cellular models, including SH-SY5Y and U87 cells, and healthy human iPSC-derived floor plate cells. We demonstrate that the I1371V mutation induces markedly more severe cellular dysfunction than G2019S. I1371V-expressing cells exhibited elevated LRRK2 autophosphorylation at S1292 and robust hyperphosphorylation of Rab8A and Rab10, indicating enhanced downstream signaling. These alterations impaired sterol trafficking, leading to selective depletion of membrane cholesterol without changes in total cellular cholesterol. Consequently, I1371V cells displayed increased membrane fluidity, disrupted microdomain organization, altered membrane topology, reduced caveolin-1 expression, and impaired dopamine transporter surface expression and dopamine uptake. Lipidomic profiling further revealed a broad disruption of lipid homeostasis, including reductions in cholesteryl esters, sterols, sphingolipids, and glycerophospholipids, whereas G2019S cells showed comparatively modest changes. Pharmacological intervention revealed mutation-specific responses, with the non-selective LRRK2 modulator GW5074 outperforming the kinase-selective inhibitor MLi-2 in restoring Rab8A phosphorylation, membrane integrity, and dopaminergic function. Collectively, these findings identify membrane lipid dysregulation as a central cell biological mechanism in LRRK2-associated PD and underscore the importance of variant-specific therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular and Cellular Drivers of Parkinson's Disease)
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11 pages, 308 KB  
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The Possible Significance of Proteomics in Understanding Molecular Mechanisms of Progressive Supranuclear Palsy, Corticobasal Degeneration, Multiple System Atrophy, and Dementia with Lewy Bodies
by Natalia Madetko-Alster, Dagmara Otto-Ślusarczyk, Marta Struga and Piotr Alster
Cells 2026, 15(9), 759; https://doi.org/10.3390/cells15090759 - 23 Apr 2026
Viewed by 302
Abstract
Atypical Parkinsonisms are a diverse group of diseases associated with multiple pathologies, including synucleinopathies and tauopathies. Atypical Parkinsonisms include progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies. The examination of these diseases is complicated due to their overlapping [...] Read more.
Atypical Parkinsonisms are a diverse group of diseases associated with multiple pathologies, including synucleinopathies and tauopathies. Atypical Parkinsonisms include progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies. The examination of these diseases is complicated due to their overlapping clinical manifestations. Hence, tools enabling reliable supplementary assessment of atypical Parkinsonisms are needed. The most common methods involve neuroimaging; however, these evaluations generally involve basic magnetic resonance imaging and indicate possible morphological changes. Less attention is given to disease background assessment. Biochemical assessment enables a more detailed examination of the factors impacting neurodegenerative processes. The features that may impact the pathophysiology of these diseases include metabolic abnormalities, excessive inflammation, and environmental factors. In this context, proteomic evaluation, as analyzed in this article, could partly address the insufficiently described aspects of the unclear pathological mechanisms related to atypical Parkinsonisms. Full article
(This article belongs to the Special Issue Molecular and Cellular Drivers of Parkinson's Disease)
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