Astrocytic Cathepsin D truncates α-synuclein and promotes Lewy neurite-like aggregation in neurons

Abstract

Parkinsons disease (PD) and related synucleinopathies are marked by the accumulation and propagation of -synuclein (-syn) aggregates, a process primarily studied in neurons. However, the contribution of astrocytes to this process remains unclear. Here, using a physiologically relevant neuron-astrocyte co-culture system that recapitulates tripartite synapse architecture, we show that astrocytes actively process and propagate -syn aggregates. Astrocytes internalize -syn pre-formed fibrils (PFFs) and cleave them into C-terminally truncated, seeding-competent species via the lysosomal protease Cathepsin D (CtsD). These truncated species are subsequently transferred to neurons, where they promote the growth of Lewy neurite (LN)-like aggregates. Notably, -syn PFF exposure disrupts lysosomal membrane integrity in astrocytes, leading to CtsD upregulation. These findings reveal a feed-forward mechanism in which astrocytic lysosomal dysfunction amplifies -syn pathogenicity. Our findings identify astrocytes as active contributors to -syn propagation and highlight the astrocytic lysosomal pathway as a potential therapeutic target in PD.