Summary of project PR002219
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 PR002219. The data can be accessed directly via it's Project DOI: 10.21228/M8SR8N This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002219 |
| Project DOI: | doi: 10.21228/M8SR8N |
| Project Title: | Biotin rescues manganese-induced parkinson's disease phenotypes and neurotoxicity |
| Project Type: | untargeted metabolomics |
| Project Summary: | Occupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson's disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying this link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adult Drosophila model of Mn toxicity to recapitulate key Parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. We performed global metabolomics on flies at an early toxicity stage and identified metabolism of the B vitamin, biotin (vitamin B7), as a master pathway underpinning Mn toxicity with systemic, body–brain increases in Mn-treated groups compared to the controls. Using BtndRNAi mutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, Parkinsonism, and mitochondrial dysfunction, while in Mn-exposed wildtype flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)-differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated levels of biotin transporters compared to healthy controls, suggesting a potential role of biotin metabolism in PD. Taken together, our findings identified the compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and Parkinsonian pathology, providing a new basis for devising effective countermeasures against manganism and PD. |
| Institute: | Columbia University |
| Department: | Department of Environmental Health Sciences |
| Laboratory: | The Miller Lab |
| Last Name: | Lai |
| First Name: | Yunjia |
| Address: | 630 West 168th Street, P&S 16-421, New York, NY 10032 |
| Email: | yunjia.lai@outlook.com |
| Phone: | 9194805489 |
| Funding Source: | National Institutes of Health |
| Publications: | Science Signaling |
Summary of all studies in project PR002219
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003589 | Metabolomics of Drosophila melanogaster under manganese (Mn) exposure (head) | Drosophila melanogaster | Columbia University | MS* | 2024-12-31 | 1 | 38 | Uploaded data (15.3G)* |
| ST003590 | Metabolomics of Drosophila melanogaster under manganese (Mn) exposure (body) | Drosophila melanogaster | Columbia University | MS* | 2024-12-31 | 1 | 38 | Uploaded data (16.6G)* |
