|Title||Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Kuo S-H, Tasset I, Cheng MM, Diaz A, Pan M-K, Lieberman OJ, Hutten SJ, Alcalay RN, Kim S, Ximénez-Embún P, Fan L, Kim D, Ko HSeok, Yacoubian T, Kanter E, Liu L, Tang G, Muñoz J, Sardi SPablo, Li A, Gan L, Cuervo AMaria, Sulzer D|
|Date Published||2022 Feb 11|
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.
|Alternate Journal||Sci Adv|