Human pericytes degrade alpha-synuclein aggregates in a strain-dependent manner

Dieriks, B. V.; Highet, B.; Alik, A.; Bellande, T.; Stevenson, T. J.; Low, V.; Park, T. I.-H.; Correia, J.; Schweder, P.; Faull, R. L. M.; Melki, R.; Curtis, M. A.; Dragunow, M.

doi:10.1101/2022.06.08.495286

bioRxiv · 10.1101/2022.06.08.495286

Human pericytes degrade alpha-synuclein aggregates in a strain-dependent manner

Dieriks, B. V.·Highet, B.·Alik, A.·Bellande, T.·Stevenson, T. J.·Low, V.·Park, T. I.-H.·Correia, J.·Schweder, P.·Faull, R. L. M.·Melki, R.·Curtis, M. A.·Dragunow, M.

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Abstract

Parkinsons disease (PD) is a progressive, neurodegenerative disorder characterised by the abnormal accumulation of -synuclein (-syn) aggregates. Central to disease progression is the gradual spread of pathological -syn. -syn aggregation is closely linked to progressive neuron loss. As such, clearance of -syn aggregates may slow the progression of PD and lead to less severe symptoms. Evidence that non-neuronal cells play a role in PD and other synucleinopathies such as Lewy body dementia and multiple system atrophy are increasing. Our previous work has shown that pericytes -- vascular mural cells that regulate the blood-brain barrier -- contain -syn aggregates in human PD brains. Here, we demonstrate that pericytes efficiently internalise fibrillar -syn irrespective of being in a monoculture or mixed neuronal cell culture. Pericytes efficiently break down -syn aggregates in vitro, with clear differences in the number of -syn aggregates/cell and average aggregate size when comparing five pure -syn strains (Fibrils, Ribbons, fibrils65, fibrils91 and fibrils110). Furthermore, pericytes derived from PD brains have a less uniform response than those derived from control brains. Our results highlight the vital role brain vasculature may play in reducing -syn burden in PD.

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Dieriks, B. V., Highet, B., Alik, A., Bellande, T., Stevenson, T. J., Low, V., Park, T. I.-H., Correia, J., Schweder, P., Faull, R. L. M., Melki, R., Curtis, M. A., Dragunow, M.. 2022-06-10. Human pericytes degrade alpha-synuclein aggregates in a strain-dependent manner. https://doi.org/10.1101/2022.06.08.495286

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