Targeting SNCA with antisense oligonucleotides for Parkinson's disease therapy: preclinical evidence

ABSTRACT: Alpha-synuclein (SNCA) accumulation is a hallmark of Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), known collectively as synucleinopathies. Current treatments remain symptomatic without addressing the underlying pathology, so therapies that reduce SNCA expression could modify disease progression. This study examines the translational potential of antisense oligonucleotides (ASOs) targeting SNCA mRNA in a physiologically relevant animal model. SNCA-targeted ASOs were administered intracerebroventricularly to two-month-old bacterial artificial chromosome (BAC) transgenic rats expressing the entire human SNCA gene locus. Forty-five days post-injection, substantial SNCA mRNA and protein decreases were detected across multiple brain regions. Transcriptomic analysis revealed decreased synaptic activity and neuronal gene expression alongside region-specific changes in glial gene profiles. Protein assays identified nuanced modulation of neuroimmune mediators and altered AKT signaling, notably reduced phosphorylation of AKT1S1/PRAS40 in the olfactory bulb and decreased activity in AKT pathway components across other brain regions. Behavioral assessments demonstrated increased mobility, enhanced exploratory behavior, and improved olfactory function in treated rats. These findings provide comprehensive molecular, cellular, and behavioral evidence supporting the advancement of SNCA-targeted ASOs as disease-modifying interventions for PD and related synucleinopathies.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE293775 | GEO | 2026/09/23

REPOSITORIES: GEO