Summary of project PR002548
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 PR002548. The data can be accessed directly via it's Project DOI: 10.21228/M8926N This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002548 |
| Project DOI: | doi: 10.21228/M8926N |
| Project Title: | Lysosomal polyamine storage upon ATP13A2 loss impairs β-glucocerebrosidase via altered lysosomal pH and electrostatic hydrolase-lipid interactions |
| Project Type: | Preclinical Mouse and cellular studies |
| Project Summary: | ATP13A2 is an endolysosomal polyamine transporter mutated in several neurodegenerative conditions involving lysosomal defects, including Parkinson’s disease (PD). While polyamines are polybasic and polycationic molecules that play pleiotropic cellular roles, their specific impact on lysosomal health is unknown. Here, we demonstrate lysosomal polyamine accumulation in ATP13A2 knockout (KO) cell lines. Primary polyamine storage caused secondary storage of lysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP) and age-dependent increase in the β-glucocerebrosidase (GCase) substrate, glucosylsphingosine, in Atp13a2 KO brains. Polyamine accumulation inhibited lysosomal GCase activity in cells and this was reversed by lysosome reacidification or BMP supplementation. A liposome-based GCase assay utilizing physiological substrates demonstrated dose-dependent inhibition of BMP-stimulated GCase activity by polyamines, in part via a pH-independent, electrostatics-based mechanism. Therefore, excess polyamine compromises lysosomes by disrupting pH and electrostatic interactions between GCase and BMP enabling efficient substrate hydrolysis, potentially clarifying their pathogenic mechanisms, and suggesting convergence on PD-relevant pathways. |
| 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 6507973837 |
Summary of all studies in project PR002548
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST004058 | Targeted Lipid and Metabolite Profiling in ATP13A2 knockout (KO) in HAP1 cells | Homo sapiens | Denali Therapeutics | MS | 2025-07-23 | 1 | 97 | Uploaded data (13.1M)* |
| ST004059 | Targeted Lipid and Metabolite Profiling in Brains of ATP13A2 Knockout Mice | Mus musculus | Denali Therapeutics | MS | 2025-07-23 | 1 | 78 | Uploaded data (55M)* |
