Abstract
Parkinson’s disease (PD) and multiple system atrophy (MSA) are caused by two distinct strains of disease-associated α-synuclein (αSynD). Recently, we have shown that olfactory mucosa (OM) samples of patients with PD and MSA can seed the aggregation of recombinant α-synuclein by means of Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC). Remarkably, the biochemical and morphological properties of the final α-synuclein aggregates significantly differed between PD and MSA seeded samples. Here, these aggregates were given to neuron-like differentiated SH-SY5Y cells and distinct inflammatory responses were observed. To deepen whether the morphological features of α-synuclein aggregates were responsible for this variable SH-SY5Y inflammatory response, we generated three biochemically and morphologically distinct α-synuclein aggregates starting from recombinant α-synuclein that were used to seed αSyn_RT-QuIC reaction; the final reaction products were used to stimulate SH-SY5Y cells. Our study showed that, in contrast to OM samples of PD and MSA patients, the artificial aggregates did not transfer their distinctive features to the αSyn_RT-QuIC products and the latter induced analogous inflammatory responses in cells. Thus, the natural composition of the αSynD strains but also other specific factors in OM tissue can substantially modulate the biochemical, morphological and inflammatory features of the αSyn_RT-QuIC products.
Highlights
Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorders belonging to a group of pathologies named α-synucleinopathies [1,2]
We have exposed neuron-like differentiated SH-SY5Y cells to αSyn fibrils generated by Real-Time Quaking-Induced Conversion (RT-QuIC) analysis of olfactory mucosa (OM)-MSA and OM-PD to evaluate whether distinct inflammatory responses were induced
As RQ-MSA and RQ-PD induced distinct inflammatory responses in neuron-like SHSY5Y cells, we evaluated the inflammatory effects of αSv1, αSv2, αSv3 and their αSyn_RT-QuIC reaction products in the same cellular model
Summary
Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorders belonging to a group of pathologies named α-synucleinopathies [1,2]. It is conceivable that αSynD may influence the morphological properties of rec-αSyn aggregates that are formed during the αSyn_RT-QuIC reaction, and this could confer them specific inflammatory properties For this reason, we have exposed neuron-like differentiated SH-SY5Y cells to αSyn fibrils generated by RT-QuIC analysis of OM-MSA and OM-PD to evaluate whether distinct inflammatory responses were induced. That might influence their seeding activity, including the possibility to transmit specific morphological properties to the reaction products For this reason, we have performed additional studies using the αSyn aggregates formed in SH-SY5Y cells stimulated with αSv1, αSv2 or αSv3 whose structure and composition could better resemble that of the natural αSynD strains. The natural αSynD strains responsible for MSA and PD (likely in combination with other still unknown factors present in the OM tissue) possess unique features which are barely reproducible using in vitro models
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