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Lewy body-like ?-synuclein aggregates resist degradation and impair macroautophagy.

ABSTRACT: Cytoplasmic ?-synuclein (?-syn) aggregates, referred to as Lewy bodies, are pathological hallmarks of a number of neurodegenerative diseases, most notably Parkinson disease. Activation of macroautophagy is suggested to facilitate degradation of certain proteinaceous inclusions, but it is unclear if this pathway is capable of degrading ?-syn aggregates. Here, we examined this issue by utilizing cellular models in which intracellular Lewy body-like ?-syn inclusions accumulate after internalization of pre-formed ?-syn fibrils into ?-syn-expressing HEK293 cells or cultured primary neurons. We demonstrate that ?-syn inclusions cannot be effectively degraded, even though they co-localize with essential components of both the autophagic and proteasomal protein degradation pathways. The ?-syn aggregates persist even after soluble ?-syn levels have been substantially reduced, suggesting that once formed, the ?-syn inclusions are refractory to clearance. Importantly, we also find that ?-syn aggregates impair overall macroautophagy by reducing autophagosome clearance, which may contribute to the increased cell death that is observed in aggregate-bearing cells.

SUBMITTER: Tanik SA

PROVIDER: S-EPMC3663539 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Lewy body-like α-synuclein aggregates resist degradation and impair macroautophagy.

Tanik Selcuk A SA Schultheiss Christine E CE Volpicelli-Daley Laura A LA Brunden Kurt R KR Lee Virginia M Y VM

The Journal of biological chemistry 20130326 21

Cytoplasmic α-synuclein (α-syn) aggregates, referred to as Lewy bodies, are pathological hallmarks of a number of neurodegenerative diseases, most notably Parkinson disease. Activation of macroautophagy is suggested to facilitate degradation of certain proteinaceous inclusions, but it is unclear if this pathway is capable of degrading α-syn aggregates. Here, we examined this issue by utilizing cellular models in which intracellular Lewy body-like α-syn inclusions accumulate after internalization ...[more]

PMID: 23532841

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Project description:Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.

Dataset Information

Lewy body-like ?-synuclein aggregates resist degradation and impair macroautophagy.

Publications

Lewy body-like α-synuclein aggregates resist degradation and impair macroautophagy.

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