التفاصيل البيبلوغرافية
| العنوان: |
Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons |
| المؤلفون: |
Hasan, Saadia, Fernandopulle, Michael S., Humble, Stewart W., Frankenfield, Ashley M., Li, Haorong, Prestil, Ryan, Johnson, Kory R., Ryan, Brent J., Wade-Martins, Richard, Ward, Michael E., Hao, Ling |
| المساهمون: |
National Institutes of Health, National Institute of Neurological Disorders and Stroke, Dementias Platform UK |
| المصدر: |
Molecular Neurodegeneration ; volume 18, issue 1 ; ISSN 1750-1326 |
| بيانات النشر: |
Springer Science and Business Media LLC |
| سنة النشر: |
2023 |
| مصطلحات موضوعية: |
Cellular and Molecular Neuroscience, Neurology (clinical), Molecular Biology |
| الوصف: |
Background Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomes remain unclear. Methods We developed multifaceted proteomic techniques to characterize the dynamic lysosomal biology in living human neurons and fixed mouse brain tissues. Using lysosome proximity labeling and immuno-purification of intact lysosomes, we characterized lysosome compositions and interactome in both human induced pluripotent stem cell (iPSC)-derived glutamatergic neurons (i 3 Neurons) and mouse brains. Using dynamic stable isotope labeling by amino acids in cell culture (dSILAC) proteomics, we measured global protein half-lives in human i 3 Neurons for the first time. Results Leveraging the multi-modal proteomics and live-cell imaging techniques, we comprehensively characterized how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes. We found that PGRN loss impairs the lysosome’s degradative capacity with increased levels of v-ATPase subunits on the lysosome membrane, increased hydrolases within the lysosome, altered protein regulations related to lysosomal transport, and elevated lysosomal pH. Consistent with impairments in lysosomal function, GRN -null i 3 Neurons and frontotemporal dementia patient-derived i 3 Neurons carrying GRN mutation showed pronounced alterations in protein turnover, such as cathepsins and proteins related to supramolecular polymerization and inherited neurodegenerative diseases. Conclusion This study suggested PGRN as a critical regulator of lysosomal pH and degradative capacity, which influences global proteostasis in neurons. Beyond the study of ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1186/s13024-023-00673-w |
| DOI: |
10.1186/s13024-023-00673-w.pdf |
| DOI: |
10.1186/s13024-023-00673-w/fulltext.html |
| الإتاحة: |
https://doi.org/10.1186/s13024-023-00673-wTest |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: |
edsbas.7BCD2EC9 |
| قاعدة البيانات: |
BASE |
