The Alpha-Synuclein RT-QuIC Products Generated by the Olfactory Mucosa of Patients with Parkinson's Disease and Multiple System Atrophy Induce Inflammatory Responses in SH-SY5Y Cells

Parkinson's disease (PD) and multiple system atrophy (MSA) are caused by two distinct strains of disease-associated alpha-synuclein (alpha Syn(D)). Recently, we have shown that olfactory mucosa (OM) samples of patients with PD and MSA can seed the aggregation of recombinant alpha-synuclein by means of Real-Time Quaking-Induced Conversion (alpha Syn_RT-QuIC). Remarkably, the biochemical and morphological properties of the final alpha-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 alpha-synuclein aggregates were responsible for this variable SH-SY5Y inflammatory response, we generated three biochemically and morphologically distinct alpha-synuclein aggregates starting from recombinant alpha-synuclein that were used to seed alpha Syn_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 alpha Syn_RT-QuIC products and the latter induced analogous inflammatory responses in cells. Thus, the natural composition of the alpha Syn(D) strains but also other specific factors in OM tissue can substantially modulate the biochemical, morphological and inflammatory features of the alpha Syn_RT-QuIC products.

Automated summary

Olfactory mucosa samples from patients with Parkinson's disease and multiple system atrophy can induce inflammatory responses by seeding the aggregation of alpha-synuclein. Distinct morphological features of alpha-synuclein aggregates can influence the inflammatory response in cells. The composition of alpha-synuclein strains and other factors in the tissue can modulate the biochemical, morphological, and inflammatory features of alpha-synuclein aggregates.