Selective α-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson's Disease

Progressive neuronal death in brainstem nuclei and widespread accumulation of alpha-synudein are neuropathological hallmarks of Parkinson's disease (PD). Reduction of alpha-synudein levels is therefore a potential therapy for PD. However, because alpha-synudein is essential for neuronal development and function, alpha-synudein elimination would dramatically impact brain function. We previously developed conjugated small interfering RNA (siRNA) sequences that selectively target serotonin (5-HT) or norepinephrine (NE) neurons after intranasal administration. Here, we used this strategy to conjugate inhibitory oligonucleotides, siRNA and antisense oligonucleotide (ASO), with the triple monoamine reuptake inhibitor indatraline (IND), to selectively reduce alpha-synudein expression in the brainstem monoamine nuclei of mice after intranasal delivery. Following internalisation of the conjugated oligonucleotides in monoamine neurons, reduced levels of endogenous alpha-synudein mRNA and protein were found in substantia nigra pars compacta (SNc), ventral tegmental area (VTA), dorsal raphe nucleus (DR), and locus coeruleus (LC). alpha-Synudein knockdown by similar to 20%-40% did not cause monoaminergic neurodegeneration and enhanced forebrain dopamine (DA) and 5-HT release. Conversely, a modest human alpha-synudein overexpression in DA neurons markedly reduced striatal DA release. These results indicate that alpha-synudein negatively regulates monoamine neurotransmission and set the stage for the testing of non-viral inhibitory oligonucleotides as disease-modifying agents in alpha-synudein models of PD.