Discovery of the lysosomal bis(monoacylglycero)phosphate synthase
Abstract/Contents
- Abstract
- Lysosomes maintain cellular homeostasis in diverse nutrient environments through the degradation and recycling of biological molecules, such as proteins, water-soluble metabolites, and lipids. As such, lysosome dysfunction underlies monogenic and complex neurodegenerative diseases. Strikingly, bis(monoacylglycero)phosphate (BMP) is a lysosome-resident glycerophospholipid that potently stimulates lysosomal catabolism, and its abundance is aberrant in neurodegeneration. Given its essential role in lysosome function, modulating BMP may ameliorate neurodegeneration; however, the enzyme responsible for its synthesis has been unknown for over a half a century, slowing progress in this field. This dissertation employs interdisciplinary tools to identify and validate the elusive BMP synthase (BMPS) and define its role in monogenic neurodegeneration. Chapter 1 explores cytopathology shared between monogenic and complex neurodegenerative diseases and establishes lysosomal storage disorders as a model for understanding neurodegeneration. Chapter 2 chronicles BMP's discovery in 1967, details both its structure-activity relationship and metabolism, and posits hypotheses for how the modulation of BMP may be therapeutically efficacious in neurodegeneration and other lysosome-associated diseases. Chapter 3 demonstrates that the Batten disease gene product CLN5 is the long-sought lysosomal BMPS and how the loss of BMP inhibits lysosomal lipid metabolism. Chapter 4 reveals that glycerophosphodiesters (GPDs) inhibit BMPS, establishing a metabolic connection between CLN3 and CLN5 Batten disease. Chapter 5 engineers an enzyme-based tool to detect and measure GPDs in diverse biological matrices. Chapter 6 looks ahead to the trajectory of the burgeoning field of BMP in health and disease. This work provides a genetic handle to study BMP and pioneers its therapeutic potential in neurodegeneration and beyond.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2024; ©2024 |
| Publication date | 2024; 2024 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Medoh, Uche Noble |
|---|---|
| Degree supervisor | Abu-Remaileh, Monther |
| Thesis advisor | Abu-Remaileh, Monther |
| Thesis advisor | Khosla, Chaitan, 1964- |
| Thesis advisor | Long, Jonathan Z |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Pfeffer, Suzanne |
| Degree committee member | Khosla, Chaitan, 1964- |
| Degree committee member | Long, Jonathan Z |
| Degree committee member | Mochly-Rosen, Daria |
| Degree committee member | Pfeffer, Suzanne |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Biochemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Uche Noble Medoh. |
|---|---|
| Note | Submitted to the Department of Biochemistry. |
| Thesis | Thesis Ph.D. Stanford University 2024. |
| Location | https://purl.stanford.edu/jm696jn8392 |
Access conditions
- Copyright
- © 2024 by Uche Noble Medoh
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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