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

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. U...

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Published in:	Neuron (Cambridge, Mass.) Vol. 110; no. 3; pp. 436 - 451.e11
Main Authors:	Stojkovska, Iva, Wani, Willayat Y., Zunke, Friederike, Belur, Nandkishore R., Pavlenko, Egor A., Mwenda, Nkatha, Sharma, Karan, Francelle, Laetitia, Mazzulli, Joseph R.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 02-02-2022
Subjects:	alpha-synuclein alpha-Synuclein - metabolism beta-glucocerebrosidase Endoplasmic Reticulum - metabolism Endoplasmic Reticulum - pathology ER stress Humans iPSC-derived midbrain dopaminergic neurons lysosomal dysfunction Mesencephalon - metabolism Mesencephalon - pathology Neurons - metabolism Neurons - pathology Parkinson Disease - metabolism Parkinson Disease - pathology Parkinson's disease protein aggregation Protein Aggregation, Pathological Protein Folding Protein Transport Proteostasis lysosomal dysfunction beta-glucocerebrosidase Parkinson's disease protein aggregation iPSC-derived midbrain dopaminergic neurons ER stress alpha-synuclein
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Summary:	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. [Display omitted] •α-Synuclein accumulation induces ER fragmentation in patient-derived midbrain neurons•α-Synuclein perturbs the neuron's ability to recognize and respond to misfolded proteins in the ER•Parkinson's neurons develop pathogenic aggregates of immature lysosomal GCase•GCase solubility/function is rescued by enhancing ER folding and downstream trafficking Stojkovska et al. found that Parkinson’s patient neurons accumulate α-synuclein and are deficient at recognizing misfolded proteins in the endoplasmic reticulum (ER), inducing pathogenic aggregation of immature lysosomal hydrolases. This phenotype is rescued by combined enhancement of ER proteostasis and protein trafficking, leading to lysosomal activation and reduction of α-synuclein.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0896-6273 1097-4199
DOI:	10.1016/j.neuron.2021.10.032