Lysosomal stress drives the release of pathogenic α-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway

Tetsuro Abe; Tomoki Kuwahara; Shoichi Suenaga; Maria Sakurai; Sho Takatori; Takeshi Iwatsubo

doi:10.1016/j.isci.2024.108893

Lysosomal stress drives the release of pathogenic α-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway

iScience. 2024 Jan 12;27(2):108893. doi: 10.1016/j.isci.2024.108893. eCollection 2024 Feb 16.

Authors

Tetsuro Abe¹, Tomoki Kuwahara¹, Shoichi Suenaga¹, Maria Sakurai¹, Sho Takatori², Takeshi Iwatsubo¹

Affiliations

¹ Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
² Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Abstract

α-Synuclein and LRRK2 are associated with both familial and sporadic Parkinson's disease (PD), although the mechanistic link between these two proteins has remained elusive. Treating cells with lysosomotropic drugs causes the recruitment of LRRK2 and its substrate Rab10 onto overloaded lysosomes and induces extracellular release of lysosomal contents. Here we show that lysosomal overload elicits the release of insoluble α-synuclein from macrophages and microglia loaded with α-synuclein fibrils. This release occurred specifically in macrophage lineage cells, was dependent on the LRRK2-Rab10 pathway and involved exosomes. Also, the uptake of α-synuclein fibrils enhanced the LRRK2 phosphorylation of Rab10, which was accompanied by an increased recruitment of LRRK2 and Rab10 onto lysosomal surface. Our data collectively suggest that α-synuclein fibrils taken up in lysosomes activate the LRRK2-Rab10 pathway, which in turn upregulates the extracellular release of α-synuclein aggregates, leading to a vicious cycle that could enhance α-synuclein propagation in PD pathology.

Keywords: Cell biology; Molecular biology.