Reduction of the α-synuclein expression promotes slowing down early neuropathology development in the Drosophila model of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterised by the formation of Lewy bodies and progressive loss of dopaminergic (DA) neurons in the substantia nigra. Lewy bodies mainly consist of α-synuclein, which plays a critical role in the pathophysiology of PD. The α-synuclein is encoded by the SNCA gene and is the first identified gene associated with hereditary PD. Currently, there are at least six disease-associated mutations in α-synuclein that cause dominantly inherited familial forms of PD. Targeted expression of human SNCA.WT/SNCA.A30P/SNCA.A53T gene in Drosophila melanogaster over specific times employing a temperature-dependent UAS/GAL4 – GAL80 system allows for the evaluation of neurodegenerative processes. In this study, SNCA was expressed only in the adult stage of Drosophila development for 1 or 2 weeks, followed by repression of gene expression for the rest of the fly’s life. It was demonstrated that the level of pathology significantly depends on the duration of α-synuclein expression. SNCA gene expression over a longer period of time caused the death of DA neurons, decreased levels of dopamine and locomotor ability. In this case, the observed neurodegenerative processes correlated with the accumulation of α-synuclein in the Drosophila brain. Importantly, repression of α-synuclein expression led to elimination of the soluble protein fraction, in contrast to the insoluble fraction. No further significant development of characteristic signs of pathology was observed after the α-synuclein expression was blocked. Thus, we suggest that reduction of α-synuclein expression alone contributes to slowing down the development of PD-like symptoms.

Keywords:

• Parkinson’s disease
• α-synuclein
• Drosophila melanogaster
• neurodegeneration

Acknowledgements

The authors thank Dr Andrew Oleinikov for critical reading of the manuscript. Stocks obtained from the Bloomington Drosophila Stock Center were used in this study.

Disclosure statement

The authors report no conflict of interest.