Constitutive translation of human α-synuclein is mediated by the 5'-untranslated region.

Pelagia Koukouraki,Epaminondas Doxakis

doi:10.1098/rsob.160022

Abstract

Genetic and biochemical studies have established a central role for α-synuclein (SNCA) accumulation in the pathogenesis of Parkinson's disease. Uncovering and subsequently interfering with physiological mechanisms that control SNCA expression is one approach to limit disease progression. To this end, the long and GC-rich 5′-untranslated region (UTR) of SNCA, which is predicted to fold into stable hairpin and G-quadruplex RNA motifs, was investigated for its role in mRNA translation. Inclusion of SNCA 5′-UTR significantly induced expression of both SNCA and luciferase ORF constructs. This effect was not associated with a change in mRNA levels or differential nucleocytoplasmic shuttling. Further, the presence of the 5′-UTR enhanced SNCA synthesis when cap-dependent translation was attenuated with rapamycin treatment. Analysis using multiple methodologies revealed that the 5′-UTR harbours an internal ribosome entry site (IRES) element that spans most of its nucleotide sequence. Signals such as plasma-membrane depolarization, serum starvation and oxidative stress stimulated SNCA protein translation via its 5′-UTR as well as enhanced its IRES activity. Taken together, these data support the idea that the 5′-UTR is an important positive regulator of SNCA synthesis under diverse physiological and pathological conditions, explaining in part the abundance of SNCA in healthy neurons and its accumulation in degenerative cells.

Highlights

Background aSynuclein (SNCA) is a neuronal protein of as yet poorly characterized function, normally found in presynaptic terminals and likely to be involved in the modulation of synaptic neurotransmission
The analysis revealed that the SNCA 50-untranslated region (UTR) significantly promotes capdependent translation and that internal ribosome entry site (IRES)-mediated translation is a mechanism by which endogenous SNCA mRNA may be translated
Analysis confirmed that the 50-UTR forms secondary structures that are largely preserved irrespective of the length of SNCA mRNA nucleotides used in the enquiry

Summary

Introduction

Synuclein (SNCA) is a neuronal protein of as yet poorly characterized function, normally found in presynaptic terminals and likely to be involved in the modulation of synaptic neurotransmission. In vitro cell culture studies indicate that the expression of mutant SNCA can sensitize neurons to toxic challenges, and viral-mediated overexpression of wild-type or mutant SNCA within nigral neurons of rodents and non-human primates has led to progressive motor dysfunction mimicking motor symptoms in PD patients [5 –7]. Taken together, these studies suggest that inhibiting SNCA expression may help ameliorate symptoms associated with PD and other synucleinopathies

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