Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking

Stojkovska I, Wani WY, Zunke F, Belur NR, Pavlenko EA, Mwenda N, Sharma K, Francelle L, Mazzulli JR (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Neuron Elsevier (Cell Press)

Book Volume: 110

Pages Range: 436-451.e11

Journal Issue: 3

DOI: 10.1016/j.neuron.2021.10.032

Abstract

Neurodegenerative disorders are characterized by a collapse in proteostasis, as shown by the accumulation of insoluble protein aggregates in the brain. Proteostasis involves a balance of protein synthesis, folding, trafficking, and degradation, but how aggregates perturb these pathways is unknown. Using Parkinson's disease (PD) patient midbrain cultures, we find that aggregated α-synuclein induces endoplasmic reticulum (ER) fragmentation and compromises ER protein folding capacity, leading to misfolding and aggregation of immature lysosomal β-glucocerebrosidase. Despite this, PD neurons fail to initiate the unfolded protein response, indicating perturbations in sensing or transducing protein misfolding signals in the ER. Small molecule enhancement of ER proteostasis machinery promotes β-glucocerebrosidase solubility, while simultaneous enhancement of trafficking improves ER morphology, lysosomal function, and reduces α-synuclein. Our studies suggest that aggregated α-synuclein perturbs the ability of neurons to respond to misfolded proteins in the ER, and that synergistic enhancement of multiple proteostasis branches may provide therapeutic benefit in PD.

Authors with CRIS profile

Friederike Zunke Juniorprofessur für Translationale Neurowissenschaften

Involved external institutions

Northwestern University US United States (USA) (US)

How to cite

APA:

Stojkovska, I., Wani, W.Y., Zunke, F., Belur, N.R., Pavlenko, E.A., Mwenda, N.,... Mazzulli, J.R. (2022). Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron, 110(3), 436-451.e11. https://doi.org/10.1016/j.neuron.2021.10.032

MLA:

Stojkovska, Iva, et al. "Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking." Neuron 110.3 (2022): 436-451.e11.

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