Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration in Drosophila

Jessika Bridi, Erika Bereczki, Saffron Smith, Goncalo Pocas, Benjamin Kottler, Pedro Domingos, Christpher Elliott, Dag Aarsland, Frank Hirth

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Abstract

Alpha-synuclein (α-syn) mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson's disease,
Parkinson's disease with dementia and dementia with Lewy bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while nonmotor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying
synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, cysteine string protein, synapsin, and syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic
active zone protein were found in patient brain samples of dementia with Lewy bodies.
Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn mediated synaptopathy is an initiating cause of agerelated neurodegeneration.
Original languageEnglish
JournalBrain Communications
DOIs
Publication statusPublished - 22 Mar 2021

Keywords

  • Parkinson’s disease; α-synuclein; active zone; synaptopathy; neurodegeneration.

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