<p>Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of <InlineEquation ID="IEq2"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Synuclein (<InlineEquation ID="IEq3"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following <InlineEquation ID="IEq4"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon <InlineEquation ID="IEq5"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Syn exposure, resulting in compromised aggregate clearance. Such a response to <InlineEquation ID="IEq6"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of <InlineEquation ID="IEq7"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Syn from neuronal cells to microglia. Microglia co-cultured with <InlineEquation ID="IEq8"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing <InlineEquation ID="IEq9"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-Syn aggregates to microglia.</p>

Impaired $\alpha$-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes

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2026年3月12日

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Ranabir Chakraborty,
Francesca Palese,
Philippa Samella,
Veronica Testa,
Jara Montero-Muñoz,
Sylvie Syan,
Takashi Nonaka,
Masato Hasegawa,
Antonella Consiglio,
Chiara Zurzolo

摘要

Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of $\alpha$ $α$ -Synuclein ( $\alpha$ $α$ -Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following $\alpha$ $α$ -Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon $\alpha$ $α$ -Syn exposure, resulting in compromised aggregate clearance. Such a response to $\alpha$ $α$ -Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of $\alpha$ $α$ -Syn from neuronal cells to microglia. Microglia co-cultured with $\alpha$ $α$ -Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing $\alpha$ $α$ -Syn aggregates to microglia.

Impaired \(\alpha\)-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes

摘要