Abstract
BackgroundOverexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD.ResultsWe have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion.ConclusionWe have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression.
Highlights
Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease postmortem
While this study focused on SNCA knockdown in the hippocampus for technical practicalities, it would be of considerable interest to determine if SNCA siRNA would be efficacious in the substantia nigra (SN), given its importance in Parkinson's disease (PD)
After modification to complement the murine sequence (Mayo8S2M), we show that direct infusion of our candidate siRNA into the hippocampi of adult mice resulted in a resilient reduction in the murine SNCA transcript level around the site of infusion as well as in more distant sites
Summary
Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease postmortem. SNCA A30P and E46K missense mutations were found to cause familial Lewy Body parkinsonism [2,3]. SNCA multiplications result in a copy-number related increase in both α-synuclein RNA and protein [8,15], and disease onset and severity are associated with gene dosage [11]. Taken together, this provides compelling evidence that SNCA overexpression can result in Lewy body parkinsonism and dementia
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