Summary of project PR002623
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002623. The data can be accessed directly via it's Project DOI: 10.21228/M8M26F This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002623 |
| Project DOI: | doi: 10.21228/M8M26F |
| Project Title: | A Common PD-Risk GBA1 Variant Disrupts LIMP2 Interaction, Impairs Glucocerebrosidase Function, and Drives Lysosomal and Mitochondrial Dysfunction |
| Project Type: | Preclinical Mouse and cellular studies |
| Project Summary: | Variants in GBA1 cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson’s disease (PD). While some GBA1 variants are associated with both GD and PD, several coding mutations, including E326K, specifically confer risk for PD. The impact of these PD-specific variants on GCase activity and lysosomal and mitochondrial function relevant to PD remains poorly understood. We show the E326K variant reduces lysosomal GCase activity by impairing its delivery to lysosomes via altered interactions with its receptor, LIMP2. Structural analyses reveal that loss of a key salt bridge between E326 and R329 underlies disrupted GCase/LIMP2 interaction in cells, as reintroduction of a negative charge at R329 rescues LIMP2 binding. Functionally, the E326K variant produces greater deficits in PD-relevant pathways than GD-linked severe GCase LoF with effects reproduced in CNS cells and human E326K carriers, providing key insights into the nature of GCase dysfunction associated with GBA1-PD. |
| Institute: | Denali Therapeutics |
| Last Name: | Suh |
| First Name: | Jung |
| Address: | 161 Oyster Point Blvd, South San Francisco, California, 94080, USA |
| Email: | suh@dnli.com |
| Phone: | +1 06507973837 |
Summary of all studies in project PR002623
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST004162 | Targeted Lipid Profiling of Mouse Brains with GBA1 E326K Loss-of-Function | Mus musculus | Denali Therapeutics | MS | 2025-09-02 | 1 | 33 | Uploaded data (1.4M)* |
| ST004163 | Targeted Lipid Profiling of HEK and iPSC derived iMG Cell Models with GBA1 Loss-of-Function | Homo sapiens | Denali Therapeutics | MS | 2025-09-02 | 1 | 169 | Uploaded data (52.2M)* |
