Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy

Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy. Kuo, S., Tasset, I., Cheng, M. M., Diaz, A., Pan, M., Lieberman, O. J., Hutten, S. J., Alcalay, R. N., Kim, S., Ximénez-Embún, P., Fan, L., Kim, D., Ko, H. S., Yacoubian, T., Kanter, E., Liu, L., Tang, G., Muñoz, J., Sardi, S. P., Li, A., Gan, L., Cuervo, A. M., & Sulzer, D. Science Advances, 8(6):eabm6393, February, 2022.
doi abstract bibtex

The most common genetic risk factors for Parkinson's disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes β-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from postmortem human GBA-PD brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.

@article{kuo_mutant_2022,
	title = {Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy},
	volume = {8},
	issn = {2375-2548},
	doi = {10.1126/sciadv.abm6393},
	abstract = {The most common genetic risk factors for Parkinson's disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes β-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from postmortem human GBA-PD brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.},
	language = {eng},
	number = {6},
	journal = {Science Advances},
	author = {Kuo, Sheng-Han and Tasset, Inmaculada and Cheng, Melody M. and Diaz, Antonio and Pan, Ming-Kai and Lieberman, Ori J. and Hutten, Samantha J. and Alcalay, Roy N. and Kim, Sangjun and Ximénez-Embún, Pilar and Fan, Li and Kim, Donghoon and Ko, Han Seok and Yacoubian, Talene and Kanter, Ellen and Liu, Ling and Tang, Guomei and Muñoz, Javier and Sardi, Sergio Pablo and Li, Aiqun and Gan, Li and Cuervo, Ana Maria and Sulzer, David},
	month = feb,
	year = {2022},
	pmid = {35138901},
	keywords = {Animals, Chaperone-Mediated Autophagy, Glucosylceramidase, Humans, Mice, Mutation, Parkinson Disease, alpha-Synuclein},
	pages = {eabm6393},
}

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