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Molecular Signatures in Overt Neurodegenerative Disease: Toward Precision Diagnosis and Classification

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: 1 January 2026 | Viewed by 864

Special Issue Editor


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Guest Editor
Department of Clinical Neuroscience (CNS), Karolinska Universitetssjukhuset, Stockholm, Sweden
Interests: spinocerebellar ataxias; polyQ disorders; Ataxin-2; molecular pathways in Alzheimer and frontotemporal dementia; epigenetics; neurogenetics of movement disorders; molecular mechanisms of spinocerebellar ataxias and other inherited neurological disorders; molecular techniques; RAN translation; circRNA; RNA processing; functional studies of genetic alterations; biomarker discovery and validation
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Special Issue Information

Dear Colleague,

This Special Issue, entitled "Molecular Signatures in Overt Neurodegenerative Disease: Toward Precision Diagnosis and Classification", aims to explore the molecular underpinnings of clinically manifest neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Spinocerebellar Ataxias, and repeat expansion disorders. We welcome the submission of studies identifying and validating diagnostic, prognostic, and stratification biomarkers that reflect disease burden, clinical heterogeneity, or therapeutic response. For this Special Issue, we are interested in biomarkers derived from non-coding RNAs, repeat expansions, proteomics, epigenetics, and advanced molecular platforms such as ddPCR, transcriptomics, and proteomics. This Special Issue also aims to highlight computational and AI-based strategies that integrate molecular data with clinical phenotypes, as well as mechanistic studies addressing signaling pathways and molecular interactions relevant to disease classification and therapeutic targeting, thereby advancing precision medicine in neurodegeneration.

Dr. Jose Miguel Laffita Mesa
Guest Editor

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Keywords

  • neurodegenerative diseases
  • molecular biomarkers
  • disease stratification
  • Parkinson’s disease
  • Alzheimer’s disease
  • spinocerebellar ataxia
  • precision medicine
  • digital PCR
  • circRNA
  • prognostic biomarkers

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Published Papers (1 paper)

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Research

28 pages, 4484 KB  
Article
Repeat Variants, Biomarkers, and Molecular Signatures in Parkinson’s Disease: ATXN2, ATXN3, CACNA1A, PRNP, TBP, C9ORF72, TOMM40, APOE, and POLG—A Swedish Perspective
by Jose Miguel Laffita-Mesa, Martin Paucar and Per Svenningsson
Int. J. Mol. Sci. 2025, 26(18), 9213; https://doi.org/10.3390/ijms26189213 - 20 Sep 2025
Viewed by 679
Abstract
Parkinson’s disease (PD), the second most common neurodegenerative disorder globally, has a notably high prevalence in Sweden (136/105). Although monogenic forms represent only a small subset of PD cases, several genetic factors—including nucleotide repeat expansions (NREs) in ATXN2, ATXN3, [...] Read more.
Parkinson’s disease (PD), the second most common neurodegenerative disorder globally, has a notably high prevalence in Sweden (136/105). Although monogenic forms represent only a small subset of PD cases, several genetic factors—including nucleotide repeat expansions (NREs) in ATXN2, ATXN3, C9ORF72, TBP, POLG, TOMM40, CACNA1A, and PRNP—have been implicated in neurodegenerative conditions with parkinsonian features. However, their contribution to PD pathogenesis in the Swedish population remains understudied. We analyzed DNA from 161 Swedish PD patients and 546 controls and evaluated clinical and CSF biomarkers (tau, phospho-tau, and β-amyloid). Intermediate ATXN2 CAG expansions were significantly associated with PD (3.40%, p = 0.0027), and novel promoter structural variations were identified. C9ORF72 G4C2 expansions were also linked to PD (2.48%, p = 0.0018), with distinct methylation patterns in PD cases. POLG Not-10/Not-11Q alleles were positively associated (9.62%, p = 0.014), while TOMM40 showed partial associations for rare genotypes (14.28%, p = 0.0014). Pathological expansions in TBP were marginally significant, while ATXN3, CACNA1A, and PRNP showed no associations. Two-way ANOVA identified significant interactions between APOE E3/E4 and POLG 10/11Q genotypes, affecting age at diagnosis (p = 0.025) and CSF β-amyloid levels. Regression highlighted tau as a key predictor of age at diagnosis (p = 0.02). Longitudinally, APOE E4 predicted cognitive decline (p = 0.015), and TOMM40 haplotypes correlated with motor deficits. In conclusion, ATXN2, C9ORF72, and POLG emerge as key genetic risk factors for PD in the Swedish population, with TOMM40 and TBP contributing partially. Altered CSF biomarker patterns support the existence of distinct molecular subtypes and warrant further investigation of novel ATXN2 variants as potential PD modifiers. Full article
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