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bioRxiv · 10.1101/2025.10.03.680233

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

Hanafusa, H.·Ohashi, K.·Shojima, H.·Hisamoto, N.·Kameyama, T.·Miyata, M.·Mizutani, K.·Takai, Y.·Matsumoto, K.
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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.

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Hanafusa, H., Ohashi, K., Shojima, H., Hisamoto, N., Kameyama, T., Miyata, M., Mizutani, K., Takai, Y., Matsumoto, K.. 2025-10-07. Astrocytic Cathepsin D truncates α-synuclein and promotes Lewy neurite-like aggregation in neurons. https://doi.org/10.1101/2025.10.03.680233

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