Objective: We aimed to understand the physiological function of alpha-synuclein (SNCA) for neuronal projections within the brain, particularly its effects on entire pathways and on individual molecular components.

Background: The gain-of-function of alpha-synuclein is a crucial driver of selective neurotoxicity in Parkinson’s disease (PD). As an early phenotype, ultrasonic vocalizations of A53T-SNCA overexpressing mice are reduced already at the postnatal stage. Conversely, in alpha-synuclein knock-out (KO) mice at the postnatal stage, the ultrasonic vocalizations are increased. Similarly, expansion mutations in the SNCA promoter result in Parkinsonian reduction of spontaneous motor activity, while shrinkage mutations in the SNCA promoter result in motor restlessness. These data suggest that a gain versus a loss in the physiological role of alpha-synuclein is relevant for the molecular mechanisms in PD, and that further analyses of alpha-synuclein KO mice are useful.

Methods: Alpha-synuclein KO mouse brains were dissected and subjected to oligonucleotide microarray analyses, comparing midbrain versus striatum versus cerebellum. Furthermore, global proteome analyses were conducted with label-free mass spectrometry and assessed by volcano plots. Biomathematical workup of the global transcriptome data was carried out with the STRING webserver in Heidelberg and the GSEA webserver in Cambridge/MA. Validation was performed with quantitative reverse-transcriptase polymerase chain reaction and immunoblots as well as immunohistochemistry.

Results: Several factors in the presynaptic and axonal compartments showed dysregulated expression. Overall, significant enrichment for pathway upregulation in EGF signaling, MEK signaling and DeltaFosB target pathways was observed in the aged striatum. As a representative molecule in the validation experiments, c-Fos mRNA was significantly dysregulated already at middle adult age.

Conclusions: Our striatum findings support the concept that synaptic plasticity in the dendritic spines is altered by the loss of presynaptic alpha-synuclein.Our striatum findings support the concept that synaptic plasticity in the dendritic spines is altered by the loss of presynaptic alpha-synuclein.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/alpha-synuclein-knock-out-mouse-brain-shows-significant-dysregulation-of-c-fos-expression/