Abstract
The protein α-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal α-synuclein burden. Here, feasibility and safety of α-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against α-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of α-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40–50% suppression of α-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in α-synuclein. Infusion with α-synuclein siRNA, while lowering α-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-α-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics.
Highlights
Several lines of evidence link the protein a-synuclein to human neurodegenerative diseases
Point mutations in the a-synuclein gene (SNCA) and increased expression of wild-type a-synuclein due to SNCA multiplication mutations are causally associated with familial forms of parkinsonism and dementia [1,2,3,4,5]. a-Synuclein is implicated in the pathogenesis of non-familial diseases such as idiopathic Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)
Post-mortem analysis assessed the effect of small interfering RNA (siRNA) administration on a-synuclein mRNA by both in situ hybridization and quantitative PCR (qPCR). a-Synuclein in situ hybridization was performed on a set of midbrain sections at the level of the exit of the 3rd nerve encompassing the mid substantia nigra
Summary
Several lines of evidence link the protein a-synuclein to human neurodegenerative diseases. A-Synuclein is implicated in the pathogenesis of non-familial diseases such as idiopathic Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). The tendency of a-synuclein to aggregate, which is well documented by both in vitro and in vivo experimental work, likely explains the formation of these neuronal and glial pathologic inclusions [10,11,12]. It may result in a gain of toxic function of the protein and contribute to neuronal injury and degeneration [10,11,12,13]
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