Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein
Cuddy LK, Wani WY, Morella ML, Pitcairn C, Tsutsumi K, Fredriksen K, Justman CJ, Grammatopoulos TN, Belur NR, Zunke F, Subramanian A, Affaneh A, Lansbury PT, Mazzulli JR (2019)
Publication Type: Journal article
Publication year: 2019
Journal
Book Volume: 104
Pages Range: 869-884.e11
Journal Issue: 5
DOI: 10.1016/j.neuron.2019.09.001
Abstract
Age-related neurodegenerative disorders are characterized by a slow, persistent accumulation of aggregated proteins. Although cells can elicit physiological responses to enhance cellular clearance and counteract accumulation, it is unclear how pathogenic proteins evade this process in disease. We find that Parkinson's disease α-synuclein perturbs the physiological response to lysosomal stress by impeding the SNARE protein ykt6. Cytosolic ykt6 is normally autoinhibited by a unique farnesyl-mediated regulatory mechanism; however, during lysosomal stress, it activates and redistributes into membranes to preferentially promote hydrolase trafficking and enhance cellular clearance. α-Synuclein aberrantly binds and deactivates ykt6 in patient-derived neurons, thereby disabling the lysosomal stress response and facilitating protein accumulation. Activating ykt6 by small-molecule farnesyltransferase inhibitors restores lysosomal activity and reduces α-synuclein in patient-derived neurons and mice. Our findings indicate that α-synuclein creates a permissive environment for aggregate persistence by inhibiting regulated cellular clearance and provide a therapeutic strategy to restore protein homeostasis by harnessing SNARE activity.
Authors with CRIS profile
Involved external institutions
Northwestern University
United States (USA) (US)
Harvard University
United States (USA) (US)
BioEnergetics LLC
United States (USA) (US)
United States (USA) (US)
Harvard University
United States (USA) (US)
BioEnergetics LLC
United States (USA) (US)
How to cite
APA:
Cuddy, L.K., Wani, W.Y., Morella, M.L., Pitcairn, C., Tsutsumi, K., Fredriksen, K.,... Mazzulli, J.R. (2019). Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein. Neuron, 104(5), 869-884.e11. https://doi.org/10.1016/j.neuron.2019.09.001
MLA:
Cuddy, Leah K., et al. "Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein." Neuron 104.5 (2019): 869-884.e11.
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