Abstract
Parkinson’s disease (PD) is an age-dependent neurodegenerative disorder. Besides characteristic motor symptoms, patients suffer from cognitive impairments linked to pathology in cortical areas. Due to obvious challenges in tracing the underlying molecular perturbations in human brain over time, we took advantage of a well-characterized PD rat model. Using RNA sequencing, we profiled the frontocortical transcriptome of post-mortem patient samples and aligned expression changes with perturbation patterns obtained in the model at 5 and 12 months of age reflecting a presymptomatic and symptomatic time point. Integrating cell type-specific reference data, we identified a shared expression signature between both species that pointed to oligodendrocyte-specific, myelin-associated genes. Drawing on longitudinal information from the model, their nearly identical upregulation in both species could be traced to two distinctive perturbance modes. While one mode exhibited age-independent alterations that affected genes including proteolipid protein 1 (PLP1), the other mode, impacting on genes like myelin-associated glycoprotein (MAG), was characterized by interferences of disease gene and adequate expression adaptations along aging. Our results highlight that even for a group of functionally linked genes distinct interference mechanisms may underlie disease progression that cannot be distinguished by examining the terminal point alone but instead require longitudinal interrogation of the system.
Highlights
Parkinson’s disease (PD) is an age-related neurodegenerative disease characterized by increasing accumulation of alpha-synuclein, encoded by the SNCA gene [1]
The well-characterized transgenic rat model we used in this study overexpresses full-length human SNCA and recapitulates typical PD features such as alpha-synuclein aggregation, progressive death of dopaminergic cells with associated motor symptoms, and neuroinflammation [15,16,17]
Using RNA sequencing (RNA-seq), we profiled the transcriptome of frontal cortex in five transgenic (TG) and five wildtype (WT) rats at both time points (Supplementary Figure 1) and determined differentially expressed genes (DEGs) along the genotype and age axis
Summary
Parkinson’s disease (PD) is an age-related neurodegenerative disease characterized by increasing accumulation of alpha-synuclein, encoded by the SNCA gene [1]. An array of cognitive www.aging-us.com deficits, including impairment of executive function, language, visuospatial/visuoconstructive abilities, memory, depression, apathy, and impulse control disorders are observed, even in early stages of PD [2,3,4,5,6]. These non-motor symptoms have been associated with disturbances of information flow through frontalsubcortical networks [7]. Through interactions with basal ganglia, the frontal cortex is involved in controlling motor functions [7]. Investigating diseaseassociated changes in frontal cortex may aid in understanding the manifestation of PD
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