# Brain region-specific and systemic transcriptomic alterations in a human alpha-synuclein overexpressing rat model

## TL;DR

This study examines how overexpression of human alpha-synuclein in rats causes specific and widespread gene expression changes in the brain and gut, offering insights into early stages of synucleinopathies.

## Contribution

The study reveals age-dependent and region-specific transcriptomic changes in a rat model of synucleinopathies, including systemic effects observed in the gut.

## Key findings

- SNCA overexpression leads to age-dependent and brain region-specific transcriptomic changes.
- A cross-regional set of differentially expressed genes was identified and partially reflected in the gut transcriptome.
- Early gene expression changes in transgenic rats align with myelination-related dysregulation seen in Parkinson's patients.

## Abstract

Synucleinopathies are age-dependent neurodegenerative diseases characterized by alpha-synuclein accumulation with distinct vulnerabilities across brain regions. Understanding early disease stages is essential to uncover initial molecular changes that might enable earlier diagnosis and causal therapy. In this study, we profiled longitudinal and brain region-resolved gene expression changes in a rat model of synucleinopathies overexpressing human SNCA. Transcriptomic analyses were performed on gene and transcript level of striatal, frontocortical, and cerebellar tissue in 5- and 12-month-old transgenic (BAC SNCA) and wild type rats revealing that SNCA overexpression leads to age-dependent transcriptomic changes that largely occur region-specific. In frontal cortex, dysregulation of myelination-associated genes agreed with Parkinson patient data as shown before. In addition, BAC SNCA rats displayed more gene expression changes at younger age, with a common and characteristic alteration pattern across all three examined brain regions. We also identified a cross-regional set of differential genes that were affected by SNCA overload. This set was also partially reflected in the gut transcriptome of the same rat model, suggesting a systemic impact of SNCA overload. Taken together, our findings highlight both brain region-specific vulnerabilities and global molecular perturbations associated with alpha-synuclein biology and provide insights into early transcriptomic changes in synucleinopathies.