Summary of Study ST004162
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
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST004162 |
| Study Title | Targeted Lipid Profiling of Mouse Brains with GBA1 E326K Loss-of-Function |
| Study Summary | Glucocerebrosidase(GCase), encoded by the GBA1 gene, is a lysosomal enzyme that degrades glucosylceramide and glucosylsphingosine, and its dysfunction is linked to Gaucher disease and Parkinson’s disease. This study applied targeted lipid profiling of GCase substrates,glucosylsphingosine and glucosylceramides, in mouse brain tissues carrying the common PD risk variant GBA1 E326K. |
| Institute | Denali Therapeutics |
| Last Name | Suh |
| First Name | Jung |
| Address | 161 Oyster Point Blvd, South San Francisco, California, 94080, USA |
| suh@dnli.com | |
| Phone | +1 06507973837 |
| Submit Date | 2025-08-29 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzML |
| Analysis Type Detail | LC-MS |
| Release Date | 2025-09-02 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Project:
| 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 |
Subject:
| Subject ID: | SU004313 |
| Subject Type: | Mammal |
| Subject Species: | Mus musculus |
| Taxonomy ID: | 10090 |
Factors:
Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)
| mb_sample_id | local_sample_id | genotype | Sample source |
|---|---|---|---|
| SA480969 | HSA-000015185 | GBA E326K HET | brain |
| SA480970 | HSA-000015187 | GBA E326K HET | brain |
| SA480971 | HSA-000015186 | GBA E326K HET | brain |
| SA480972 | HSA-000015190 | GBA E326K HET | brain |
| SA480973 | HSA-000015188 | GBA E326K HET | brain |
| SA480974 | HSA-000015184 | GBA E326K HET | brain |
| SA480975 | HSA-000015189 | GBA E326K HET | brain |
| SA480976 | HSA-000015193 | GBA E326K HET | brain |
| SA480977 | HSA-000015191 | GBA E326K HET | brain |
| SA480978 | HSA-000015192 | GBA E326K HET | brain |
| SA480979 | HSA-000015179 | GBA E326K HOM | brain |
| SA480980 | HSA-000015174 | GBA E326K HOM | brain |
| SA480981 | HSA-000015180 | GBA E326K HOM | brain |
| SA480982 | HSA-000015181 | GBA E326K HOM | brain |
| SA480983 | HSA-000015177 | GBA E326K HOM | brain |
| SA480984 | HSA-000015183 | GBA E326K HOM | brain |
| SA480985 | HSA-000015175 | GBA E326K HOM | brain |
| SA480986 | HSA-000015182 | GBA E326K HOM | brain |
| SA480987 | HSA-000015176 | GBA E326K HOM | brain |
| SA480988 | HSA-000015178 | GBA E326K HOM | brain |
| SA480989 | HSA-000015287 | NA | brain |
| SA480990 | HSA-000015288 | NA | brain |
| SA480991 | HSA-000015204 | NA | brain |
| SA480992 | HSA-000015199 | WT | brain |
| SA480993 | HSA-000015198 | WT | brain |
| SA480994 | HSA-000015200 | WT | brain |
| SA480995 | HSA-000015195 | WT | brain |
| SA480996 | HSA-000015197 | WT | brain |
| SA480997 | HSA-000015196 | WT | brain |
| SA480998 | HSA-000015203 | WT | brain |
| SA480999 | HSA-000015194 | WT | brain |
| SA481000 | HSA-000015201 | WT | brain |
| SA481001 | HSA-000015202 | WT | brain |
| Showing results 1 to 33 of 33 |
Collection:
| Collection ID: | CO004306 |
| Collection Summary: | All animal procedures were performed in accordance with a protocol approved by the Institutional Animal Care and Use Committee of the National Institute on Aging, NIH. Wildtype, homozygous and heterozygous E326K GBA1 knock-in (KI) male and female mice raised on a C57Bl/6 background were bred in-house on a 12-hr day/night cycle for the following experiments. All mice were supplied with Rodent NIH-07 diet and water ad libitum. The brain was then removed and one hemisphere retained without sub-dissection. Tissue samples were individually weighed, flash frozen on dry ice and stored at -80°C for subsequent analysis. |
| Sample Type: | Brain |
| Storage Conditions: | -80℃ |
| Collection Vials: | Lobind 1.5 mL Eppendorf tubes |
| Storage Vials: | Lobind 1.5 mL Eppendorf tubes |
Treatment:
| Treatment ID: | TR004322 |
| Treatment Summary: | No treatment |
Sample Preparation:
| Sampleprep ID: | SP004319 |
| Sampleprep Summary: | 20 (± 3) mg of brain tissues were weighed and flash frozen during tissue collection. Lipids were extracted from the frozen samples using 400 mL of HPLC-grade methanol (Fisher Chemical; # A452-4) containing stable-isotope internal standards and homogenized with a 3 mm tungsten carbide bead for 30 s at 25 Hz on TissueLyzer II (QIAGEN, #85300). The methanol fraction was isolated via centrifugation (20 min at 4°C, 21,000 x g, transferred to a 96-well sample collection plate (Waters; #186005837) and incubated for 1 h, at -20°C for protein precipitation, followed by an additional 20 min centrifugation (4,000 x g at 4°C). The supernatant was transferred to glass vial plates (Analytical systems, #27350) for LCMS analysis. |
| Processing Storage Conditions: | On ice |
| Extract Storage: | -20℃ |
Chromatography:
| Chromatography ID: | CH005246 |
| Instrument Name: | Agilent 1290 Infinity II |
| Column Name: | Advanced Material Technology HALO HILIC (150 x 3.0mm, 2um) |
| Column Temperature: | 45 |
| Flow Gradient: | 0.0–2.0 min, 100% B; 2.1 min, 95% B; 4.5 min, 85% B; held at 85% B until 6.0 min; 6.1 min, 0% B; held at 0% B until 8.5 min |
| Flow Rate: | 0.45 mL/min |
| Solvent A: | 92.5% acetonitrile/5% isopropanol/2.5% water; 5 mM ammonium formate; 0.5% formic acid |
| Solvent B: | 92.5% water/5% isopropanol/2.5% acetonitrile; 5 mM ammonium formate; 0.5% formic acid |
| Chromatography Type: | HILIC |
Analysis:
| Analysis ID: | AN006907 |
| Analysis Type: | MS |
| Chromatography ID: | CH005246 |
| Num Factors: | 4 |
| Num Metabolites: | 39 |
| Units: | normalized peak area |
