| First Author | Kuo SH | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 6 | Pages | eabm6393 |
| PubMed ID | 35138901 | Mgi Jnum | J:358095 |
| Mgi Id | MGI:7765054 | Doi | 10.1126/sciadv.abm6393 |
| Citation | Kuo SH, et al. (2022) Mutant glucocerebrosidase impairs alpha-synuclein degradation by blockade of chaperone-mediated autophagy. Sci Adv 8(6):eabm6393 |
| abstractText | 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 beta-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 alpha-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 alpha-synuclein accumulation. |
