Brain region-resolved pharmacodynamics of a human SNCA 3′UTR-targeting antisense oligonucleotide in BAC-hSNCA rats
Brain region-resolved pharmacodynamics of a human SNCA 3′UTR-targeting antisense oligonucleotide in BAC-hSNCA rats
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Original abstract
Abstract Background Alpha-synuclein (SNCA) accumulation contributes to Parkinson’s disease (PD), and lowering SNCA expression is a candidate disease-modifying approach. The brain-wide pharmacodynamic profile of human-targeting antisense oligonucleotides (ASOs) remains incompletely defined in humanized models that preserve the regulatory architecture of the human SNCA locus. Methods BAC-h SNCA rats were treated at an early stage when human SNCA is elevated, but striatal dopamine content remains largely preserved. A single intracerebroventricular dose of a human SNCA 3′UTR-targeting ASO (SNCA ASO3.0) was administered, and outcomes were assessed 45 days later by isoform-specific qPCR, immunoblotting of soluble and detergent-insoluble SNCA species, bulk RNA-seq across selected regions, multiplex cytokine profiling, phospho-kinase assays, neurotransmitter quantification, and behavioral testing. Results SNCA ASO3.0 reduced human SNCA mRNA and multiple SNCA protein species in a regionally graded manner, with the strongest effects in the olfactory bulb and striatum. Bulk RNA-seq identified anatomically distinct transcriptional responses, including synaptic and metabolic pathway shifts in olfactory bulbs and immune-related enrichment within glial signatures in striatum and midbrain, without detectable changes in GFAP or IBA1 protein. Cytokine profiling showed selective modulation of a subset of analytes, and phospho-kinase assays indicated reduced AKT1S1/PRAS40 phosphorylation. Striatal dopamine levels were unchanged, whereas striatal tyrosine hydroxylase increased. SNCA ASO3.0 increased locomotor activity, exploratory behavior, and selected measures of olfactory discrimination. Conclusions Partial suppression of human SNCA in a humanized rat model yields region-specific molecular adaptations accompanied by early behavioral changes at a stage preceding overt dopamine depletion. These data provide a framework for evaluating region-resolved consequences of SNCA-lowering interventions in synucleinopathies.