Brain Region-Specific Expression Levels of Synuclein Genes in an Acid Sphingomyelinase Knockout Mouse Model: Correlation with Depression-/Anxiety-Like Behavior and Locomotor Activity in the Absence of Genotypic Variation.

Abstract

Accumulating evidence suggests an involvement of sphingolipids, vital components of cell membranes and regulators of cellular processes, in the pathophysiology of both Parkinson's disease and major depressive disorder, indicating a potential common pathway in these neuropsychiatric conditions. Based on this interaction of sphingolipids and synuclein proteins, we explored the gene expression patterns of α-, β-, and γ-synuclein in a knockout mouse model deficient for acid sphingomyelinase (ASM), an enzyme catalyzing the hydrolysis of sphingomyelin to ceramide, and studied associations with behavioral parameters. Normalized,, andgene expression was determined by quantitative PCR in twelve brain regions of sex-mixed homozygous (ASM-/-,= 7) and heterozygous (ASM+/-,= 7) ASM-deficient mice, along with wild-type controls (ASM+/+,= 5). The expression of all three synuclein genes was brain region-specific but independent of ASM genotype, with β-synuclein showing overall higher levels and the least variation. Moreover, we discovered correlations of gene expression levels between brain regions and depression- and anxiety-like behavior and locomotor activity, such as a positive association betweenmRNA levels and locomotion. Our results suggest that the analysis of synuclein genes could be valuable in identifying biomarkers and comprehending the common pathological mechanisms underlying various neuropsychiatric disorders.