Abstract
α-Synuclein (α-Syn) protein is involved in the pathogenesis of Parkinson’s disease (PD). Point mutations and multiplications of the α-Syn, which encodes the SNCA gene, are correlated with early-onset PD, therefore the reduction in a-Syn synthesis could be a potential therapy for PD if delivered to the key affected neurons. Several experimental strategies for PD have been developed in recent years using oligonucleotide therapeutics. However, some of them have failed or even caused neuronal toxicity. One limiting step in the success of oligonucleotide-based therapeutics is their delivery to the brain compartment, and once there, to selected neuronal populations. Previously, we developed an indatraline-conjugated antisense oligonucleotide (IND-1233-ASO), that selectively reduces α-Syn synthesis in midbrain monoamine neurons of mice, and nonhuman primates. Here, we extended these observations using a transgenic male mouse strain carrying both A30P and A53T mutant human α-Syn (A30P*A53T*α-Syn). We found that A30P*A53T*α-Syn mice at 4–5 months of age showed 3.5-fold increases in human α-Syn expression in dopamine (DA) and norepinephrine (NE) neurons of the substantia nigra pars compacta (SNc) and locus coeruleus (LC), respectively, compared with mouse α-Syn levels. In parallel, transgenic mice exhibited altered nigrostriatal DA neurotransmission, motor alterations, and an anxiety-like phenotype. Intracerebroventricular IND-1233-ASO administration (100 µg/day, 28 days) prevented the α-Syn synthesis and accumulation in the SNc and LC, and recovered DA neurotransmission, although it did not reverse the behavioral phenotype. Therefore, the present therapeutic strategy based on a conjugated ASO could be used for the selective inhibition of α-Syn expression in PD-vulnerable monoamine neurons, showing the benefit of the optimization of ASO molecules as a disease modifying therapy for PD and related α-synucleinopathies.
Highlights
In the elderly population, Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease [1,2]
Since the A30P and A53T familial point tations in the SNCA gene are a risk factor for early-onset PD [9,10,37], we examined mutations in the SNCA gene are a risk factor for early-onset PD [9,10,37], we examined the anxiety-depressive phenotype and cognitive abnormalities, as well as DA function in the anxiety-depressive phenotype and cognitive abnormalities, as well as DA function in middle-aged mice (5 months), as these features have not been assessed in previous studies middle-aged mice (5 months), as these features have not been assessed in previous studies using this transgenic mouse model
Human α-Syn knockdown in monoaminergic nuclei normalized the nigrostriatal DA neurotransmission in the A30P*A53T*α-Syn transgenic mice, the current IND-1233-antisense oligonucleotides (ASO) therapy could not significantly reverse the behavioral phenotype, perhaps due to an insufficient time/dose and/or the involvement of downstream changes in relevant brain circuits not recovered by the treatment
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease [1,2]. Preclinical studies in rodents and nonhuman primates have successfully shown that α-Syn can be downregulated in PD-affected brain areas after direct application of oligonucleotide therapeutics including antisense oligonucleotides (ASO), small interfering RNAs (siRNA), and microRNAs (miRNA) [24,25,26,27,28,29,30,31] Irrespective of these potential hitches, a major limitation in the development of oligonucleotide-based therapeutics is their delivery to the brain compartment, and once there, to selected neuronal populations or cell types. We extended these obof 20 servations and assessed whether an IND-1233-ASO sequence designed in such a way that the target mRNA sequence displays homology with the murine, rhesus macaque, and human α-Syn is able to downregulate h-α-Syn expression in DA and NE brain areas of transgenic A30P*A53T*α-Syn mice.
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