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bioRxiv · 10.1101/2023.10.23.563557

Reduction of a-synuclein aggregates by PIKfyve inhibition via TFEB-mediated lysosomal biogenesis in a Parkinson disease model

Lucas-Del-Pozo, S.·Uras, G.·Fierli, F.·Lentini, V.·Koletsi, S.·Chau, K.-Y.·Hughes, D.·Schapira, A. H.
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Abstract

Parkinson disease is a neurodegenerative disorder characterised by impairment of motor function, and is associated with a progressive accumulation of insoluble aggregates of misfolded alpha-synuclein. In the present study, we exploited the SH-SY5Y cell model overexpressing a pro-aggregation form of alpha-synuclein to investigate the efficacy of PIKfyve-mediated lysosomal biogenesis, through TFEB, as potential target for Parkinson therapy. To investigate this, we exploited high-content imaging along with enzymatic assays to follow the progression of lysosomal biogenesis, lysosomal function and alpha-synuclein accumulation. The cellular model exploited in this study recapitulated important elements of the biochemical phenotype observed in Parkinson patient-derived neurons, including synuclein aggregates and impaired glucocerebrosidase (GCase) function. PIKfyve inhibition by YM201636 resulted in a lysosomal-dependant reduction of alpha-synuclein aggregates as early as 24 hours post-treatment. The mechanism of action of YM201636 was shown to be TFEB-mediated, with an increase in TFEB in the nuclei which subsequently resulted in increased lysosomal markers LAMP1 and GCase. PIKfyve inhibtion efficacy was also tested in differentiated SH-SY5Y cells, exhibiting a neuron-like morphology. In these cells, YM201636 also significantly reduced alpha-synuclein aggregates and increased TFEB nuclear presence. These findings suggest that PIKfyve inhibition could be exploited as therapeutic target for Parkinson disease.

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Lucas-Del-Pozo, S., Uras, G., Fierli, F., Lentini, V., Koletsi, S., Chau, K.-Y., Hughes, D., Schapira, A. H.. 2023-10-24. Reduction of a-synuclein aggregates by PIKfyve inhibition via TFEB-mediated lysosomal biogenesis in a Parkinson disease model. https://doi.org/10.1101/2023.10.23.563557

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