Blood-based DNA repair and stress response signals reveal a short molecular window prior to diagnosis of Parkinson’s disease.

study: Longitudinal assessment of DNA repair signature trajectories in prodromal and established Parkinson’s disease. Image credit: Chinnapong/Shutterstock.com

In a recent study published in npj parkinson’s diseaseresearchers examined the stress response integrated with DNA repair (ISR) Genes of healthy people and patients with prodromal and established Parkinson’s disease (PD).

DNA damage and repair appears early in Parkinson’s disease progression

PD It is a progressive neurodegenerative disease characterized by motor symptoms such as bradykinesia, postural instability, tremor, and rigidity, which appear only after significant neurodegeneration. Several years before symptoms develop, people experience a prodromal phase characterized by non-motor features such as anosmia, anxiety, depression, constipation, and rapid eye movement sleep behavior disorder.

Understanding molecular changes and mechanisms in prodromal symptoms PD This is of great importance as it may allow diagnosis before significant neuronal loss occurs, when intervention is most likely to be effective. Evidence suggests that oxidative DNA damage and maladaptive or impaired repair responses PD Pathogenesis from the early stages. In this way, the progenitor PD Patients may show obvious changes in their repair pathways before clinical symptoms appear.

Tracking DNA repair dynamics in PD with longitudinal blood transcriptomics

In this study, researchers investigated the dynamic regulation of DNA repair gene expression, a prodromal condition, in healthy individuals. PD personal and established PD patient. Subjects included 188 healthy individuals and 58 progenitors. PD Individuals and Founders 393 PD We analyzed peripheral blood transcriptome data from patients in the Parkinson’s Disease Progression Markers Initiative cohort.

First, we examined the overall differential expression pattern across groups at baseline. Number of differentially expressed genes (DEG) gradually increased across comparisons from no significant difference between the healthy and progenitor groups to a large difference between the healthy and established groups. PD groups, and between precursors and establishments. PD group.

It should be noted that ISRnuclear DNA damage repair (dna rep), and mitochondrial DNA damage repair (mtDNArep) routes were hardly present in the top 50 DEG. Next, the research team assessed whether longitudinal gene expression patterns existed within the cells. ISR, dna repand mtDNArep May be able to differentiate established routes PD A machine learning classification model applied to repeated follow-up visits is used to extract patients from healthy people.

Classification accuracy assessed at baseline, 12, 24, and 36 months ranged from 50% to 64% at each time point. This means that the expression of these pathways in peripheral blood does not provide a strong enough signal to differentiate. PD From healthy control. In contrast, accuracy was high when distinguishing between prodromal and prodromal symptoms. PD Post-baseline classification performance remained relatively weak, but healthy individuals were detected across the three gene sets post-baseline.

Accuracy steadily improved over time mtDNArep gene set, peaking at 36 months (89%). Variation in gene expression was highest at baseline and decreased over time. This suggests that gene expression becomes more uniform in individuals with prodromal symptoms as the disease progresses. The authors interpret this pattern as a transient, potentially adaptive transcriptional response that decreases over time. PD progress. Furthermore, classification accuracy was high between established and progenitor PD group.

However, accuracy decreased slightly at later time points, suggesting that differences in gene expression decrease as the disease progresses. The team also evaluated a known core set. PDRelated genes and broader genes PD– a set of related genes to compare their classification ability with their classification ability ISR and DNA repair pathways. these PD-Specific gene sets could not reliably distinguish between healthy and established people PD patient.

Nevertheless, PDThe specific gene set discriminated between healthy controls and individuals with prodromal symptoms with an accuracy ranging from 65% to 87%. Similar to other gene sets, classification accuracy was low at baseline and decreased at subsequent visits. of PD-Specific gene sets also performed better in differentiating between prodromal and established prodromal individuals. PD.

The team then assessed how gene expression changed over time in each group. Gene expression was relatively stable in healthy, established individuals PD Grouped over time. However, the progenitor group showed greater variation and was highest at baseline. Furthermore, many genes in the progenitor group showed dynamic, nonlinear trends over time, and about half of the DNA repair genes and nearly three-quarters of the DNA repair genes showed dynamic, nonlinear trends over time. ISR Genes exhibit nonlinear trajectories.

Finally, we performed feature importance analysis to identify genes contributing most to group separation. This revealed several predictors of prodromal symptoms PDincluding excision-repair complementary group 6 (ERCC6), primase polymerase (prim paul), Nth-like DNA glycosylase 1 (NTHL1), Nei-like DNA glycosylase 2 (neil 2).

Early Parkinson’s disease shows temporary but detectable molecular signatures

In summary, this study ISR DNA repair gene expression during the prodromal stage PD. The results reveal distinct molecular changes that occur before clinical diagnosis. PDrevealing candidate molecular signatures that may help stratify early-stage disease.

However, the authors caution that peripheral blood manifestations are an indirect surrogate for brain pathology, that immune-related signals may influence the observed patterns, and that not all people with prodromal symptoms convert to clinical symptoms. PDand changes in transcript levels may not directly reflect protein function. Future studies should validate these results in larger cohorts, investigate the underlying biological mechanisms, and assess diagnostic and therapeutic potential.

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