| Gene Symbol | ent-gene-694200ea |
| Loss-of-function (LoF) alleles | N370S, L444P, 84insGG, Rec1 (del55), and many others. |
| Missense mutations | E326K, T369M, which are common in European populations. |
| Complex alleles | recombinant alleles that can have variable enzymatic activity. |
| Reaction | GlcCer + H2O → Ceramide + Glucose. |
| Location | Lysosomal lumen, mediated by the integral membrane protein GCase, which requires the co-factor **saposin C** for optimal activity. |
| Saposin C | co-factor; deficiency leads to a variant of GD. |
| LIMP-2 (SCARB2) | transports GCase from the ER to the lysosome. |
| GCase substrate GlcCer | accumulation impairs lysosomal membrane integrity and can cause **ER stress**[@mazzulli2011]. |
| Cathepsin D (CTSD) | the principal protease for alpha-synuclein degradation – shows reduced activity in GBA-deficient neurons. |
| Macroautophagy | Impaired flux prevents efficient clearance of alpha-synuclein aggregates. |
| Chaperone-mediated autophagy (CMA) | GCase deficiency down-regulates LAMP-2A, reducing CMA activity[@avenali2020]. |
| Proteasomal degradation | Ceramide accumulation can inhibit the 26S proteasome, contributing to a "double-hit" on protein clearance. |
| Kinase activity cross-regulation | GCase deficiency leads to accumulation of glucosylceramide, which directly activates LRRK2 kinase activity through lipid raft reorganization and Rab phosphorylation cascades. |
| Lysosomal trafficking impairment | LRRK2-mediated phosphorylation of Rab7 and Rab10 disrupts lysosomal trafficking in GBA-deficient neurons, creating a "double-hit" on autophagy[@liu2021]. |
| Synergistic effects on alpha-synuclein | Combined GBA loss and LRRK2 hyperactivity dramatically accelerates alpha-synuclein aggregation. |
| KG Connections | 4 knowledge graph edges |
| Databases | GeneCardsUniProtNCBI GeneHPASTRING |
No AI portrait yet
No comments yet. Be the first to comment!