Sulev Koks

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p < 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p < 0.05 and 74 proteins with FDR < 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.

Wolfram syndrome is a rare childhood neurodegenerative disease characterized by diabetes followed by severe and rapid optic atrophy leading to blindness before the age of 20. Patients often develop other symptoms, such as deafness and neurological dysfunction. Wolfram syndrome is caused by mutations in the WFS1 gene, which encodes wolframin protein. Despite decades of intensive research, the complex mechanisms of optic neuropathy are not fully understood, and there are currently no therapies to prevent vision loss in Wolfram patients. Here, we showed that the Wfs1 knockout mice produced by the Estonian group, in which exon 8 of the Wfs1 gene was disrupted, exhibit a progressive loss of visual acuity, optic disc pallor and severe optic nerve damage. We tested the efficiency of gene therapy using AAV2 to deliver human WFS1 to retinal ganglion cells in Wfs1 knockout mice. Our results provide the first evidence that intravitreal injection of human WFS1 has significant neuroprotective effects on retinal ganglion cells and their axons and slows the loss of visual acuity. These results demonstrate that WFS1 is able to provide both functional and structural protection to retinal ganglion cells in Wfs1 knockout mice and provide important evidence for the efficacy of WFS1 as a neuroprotective treatment for Wolfram syndrome. These results demonstrate the promising effects of gene therapy for Wolfram syndrome and encourage future research aimed at conducting clinical trials in patients.

Background/Objectives: Parkinson’s disease (PD) is associated with systemic molecular alterations that extend beyond the central nervous system, including changes in peripheral blood transcriptomic profiles. While prior studies have focused predominantly on coding-gene expression, the longitudinal behavior of the peripheral blood repeatome following clinical diagnosis remains poorly characterized. Here, we investigated temporal remodeling of repetitive-element transcription over 36 months post-diagnosis by integrating repeat subfamily- and locus-specific analyses. Methods: Repeatome expression was quantified using SalmonTE and DESeq2 in peripheral blood RNA-seq data from 1560 PD and control individuals at diagnostic baseline (BL) and four follow-up visits (6, 12, 24, and 36 months). Differential expression was assessed at the subfamily level, with additional locus-specific validation in a representative subset. Results: A total of 259 repeat subfamilies were differentially expressed (padj < 0.05), of which 224 (86.5%) were already detected at baseline. Enrichment of differential expression was significantly higher at baseline than at later visits (odds ratio = 30.9, p < 2.2 × 10−16), with limited additional divergence over time. Longitudinal analyses revealed non-linear trajectories in selected repeat families, including Alu and SVA subfamilies. Locus-specific analysis identified 237 significantly regulated elements, demonstrating heterogeneous, site-specific transcriptional changes, including clusters of differentially expressed loci and instances within PD-relevant genomic regions (e.g., SNCA and IKZF2). Conclusions: Peripheral blood repeatome expression differs between PD and control groups, with the dominant signal established at clinical diagnosis and modest longitudinal modulation thereafter. Integration of locus-level analysis indicates that subfamily level patterns arise from discrete genomic events rather than uniform regulation. These findings support a model of systemic, immune-associated transcriptomic remodeling in circulating blood cells and position the peripheral repeatome as a dynamic framework for biomarker discovery and future mechanistic investigation.

To investigate whether antidiabetic drugs have a biological basis to be repurposed in PD prevention, we applied a drug target Mendelian randomization framework to assess associations between genetic variation in antidiabetic drug targets and PD risk or age at onset (AAO). Instrumental variables (IVs) were derived from GWAS summary statistics on fasting glucose (FG), glycated hemoglobin (HbA1c), and gene expression data from GTEx. Apart from SGLT2 inhibitors, all other antidiabetic drugs of interest could be instrumented through our methods. Positive and negative control analyses were carried out to validate 20 IVs in the FG arm and 23 IVs in the HbA1c arm. DPP-4 inhibitors failed the positive control. GWAS summary statistics for PD risk and AAO data were sourced from the IPDGC and COURAGE-PD consortia, resulting in 42 083 cases/457 090 controls for risk and 37 103 PD cases for AAO. MR analyses showed no significant associations across consortia or in meta-analysis. These findings do not support a causal role of genetic variation in antidiabetic drug targets in PD risk or AAO.

Progression from Parkinson's disease (PD) to Lewy body dementia is a major clinical concern. Although several progression-associated loci have been identified, their cumulative effects on cognitive decline have not been systematically evaluated. To assess the dose-dependent effect of five candidate progression loci linked to synaptic vulnerability (RIMS2, TMEM108, GBA1) and amyloid-tau pathology (APOE, WWOX), we analyzed 7745 participants from 24 cohorts with 28,737 longitudinal visits over 15 years using random-effects meta-analyses of cohort-specific Cox proportional hazards models. Dementia risk increased monotonically with the number of progression loci (0, 1, 2, or ≥3). A single locus conferred a 1.56-fold increase in risk (hazard ratio (HR) = 1.56, 95% CI: 1.28-1.89), rising to 3.21-fold for two loci (HR = 3.21, 95% CI: 2.19-4.70) and 7.49-fold for three or more loci (HR = 7.49, 95% CI: 4.98-11.28). Individually, GBA1 (HR = 2.09), APOE ε4 (HR = 1.71), RIMS2 (HR = 1.90), TMEM108 (HR = 2.05), and WWOX (HR = 1.56) were associated with dementia risk, but there was heterogeneity between clinical trials, biomarkers, and population-based cohorts. Multi-locus dosage increases dementia risk in a monotonic manner and may improve stratification and clinical trial design in PD.

Correction to: npj Parkinson’s Disease https://doi.org/10.1038/s41531-025-01180-z, published online 02 December 2025

In this article, the author list for the Global Parkinson’s Genetic Program (GP2) consortium was incomplete. The full list of GP2 consortium members has now been provided in the Supplementary Information.

Epilepsy is one of the most common neurological diseases in the world, but it is also complex and difficult to study. There is a significant genetic component to epilepsy and more information is being published frequently. It is difficult to group and summarise all of this information in a way that is beneficial for both researchers and clinicians. The aim of this paper is to create a summary of all currently known epilepsy associated genes in order to aid epilepsy research to better understand the aetiology of the disease. This was achieved through gathering genetic data from three databases: Online Mendelian Inheritance in Man (OMIM), Clincal Genome (ClinGen), and PubMed. Genes were filtered based on specific criteria and were summarised into three tables: Epilepsy genes, Epilepsy associated genes and Predicted epilepsy associated genes. A fourth table was produced to showcase all epilepsy genes that were identified in all three databases. A total of 2,536 genes were identified to have some level of association with epilepsy. A total of 238 genes were classified as Epilepsy genes, 1,317 genes were classified as Epilepsy associated genes and 981 genes were classified as Predicted epilepsy genes. Finally, 86 genes were identified to be epilepsy genes that were found in all three genetic databases and represent the highest confidence in association with epilepsy. The significance of this study involves the ability to give researchers an up-to-date list of genes that have an association to epilepsy and a summary of information about said genes.

We investigated the role of copy number variations (CNVs) in Parkinson's disease (PD) using genotyping data from 10,815 patients (2731 early-onset PD, EOPD) and 8901 controls from the COURAGE-PD consortium. CNVs were analyzed using a sliding window genome-wide association and burden approach. No genome-wide significant CNVs were detected in the overall cohort, but a robust deletion spanning exons 2-6 of PRKN was identified in EOPD cases, validated by MLPA, and replicated in the GP2 dataset (23,089 cases, 18,824 controls). CNV burden was significantly enriched in PD-related genes, primarily driven by PRKN, with the strongest effect observed in EOPD. PRKN CNV carriers showed earlier age at onset, confirmed by survival analysis. No association was observed for genome-wide or large CNV burden. Our findings reinforce the pivotal role of PRKN deletions in early-onset PD and highlight the need for high-resolution CNV analysis in large cohorts to uncover additional rare contributors to PD risk.

Common and rare variants in LRRK2 influence Parkinson's disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66-5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.