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

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Synucleinopathies are age-dependent neurodegenerative diseases.
• Alpha-synuclein (SNCA) accumulation is a hallmark.
• Early molecular changes are crucial for diagnosis and therapy.

Purpose of the Study:

• To profile longitudinal, region-specific gene expression in a rat model of synucleinopathies.
• To identify early molecular alterations associated with SNCA overexpression.
• To investigate potential systemic effects of SNCA overload.

Main Methods:

• Transcriptomic analysis (gene and transcript level) of striatal, frontocortical, and cerebellar tissues.
• Comparison of 5- and 12-month-old transgenic (BAC SNCA) and wild-type rats.
• Analysis of gut transcriptome.

Main Results:

• SNCA overexpression induced age-dependent and region-specific transcriptomic changes.
• Early gene expression alterations were observed across multiple brain regions.
• Dysregulation of myelination-associated genes in the frontal cortex mirrored Parkinson's patient data.
• A common set of differentially expressed genes was identified across brain regions and partially in the gut.

Conclusions:

• SNCA overload causes both brain region-specific vulnerabilities and global molecular perturbations.
• Early transcriptomic changes provide insights into synucleinopathy development.
• Findings suggest a systemic impact of SNCA overload, potentially affecting the gut.