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The Role of Lysosomal Cholesterol Tr...

Davis, Oliver Brayer.

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The Role of Lysosomal Cholesterol Transport in Cellular Nutrient Sensing and Organelle Homeostasis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Role of Lysosomal Cholesterol Transport in Cellular Nutrient Sensing and Organelle Homeostasis./
作者:	Davis, Oliver Brayer.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	89 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-05, Section: B.
Contained By:	Dissertations Abstracts International82-05B.
標題:	Biology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28090550
ISBN:	9798691239229

The Role of Lysosomal Cholesterol Transport in Cellular Nutrient Sensing and Organelle Homeostasis.
Davis, Oliver Brayer.

The Role of Lysosomal Cholesterol Transport in Cellular Nutrient Sensing and Organelle Homeostasis. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 89 p.

Source: Dissertations Abstracts International, Volume: 82-05, Section: B.

Thesis (Ph.D.)--University of California, Berkeley, 2020.

This item must not be sold to any third party vendors.

Lysosomes are the main catabolic organelles of a eukaryotic cell and are critical for maintenance of cellular homeostasis. Macromolecules, organelles captured via autophagy, and material taken up by endocytosis are degraded in lysosomes. Consequently, lysosomes concentrate, store, recycle, and distribute metabolites crucial for biosynthetic processes. The lysosome also functions as a platform for regulating and coordinating signaling pathways. In particular, a master regulator of cell growth and proliferation - the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved serine/threonine protein kinase - is activated at the surface of the lysosome when nutrients are plentiful (e.g., amino acids potently promote mTORC1 activity). Cholesterol, a key component of biomembranes, also stimulates mTORC1 recruitment and activation at the lysosome. Thus, by integrating its degradative and signaling roles, the lysosome serves as a hub for nutrient sensing.In diseases known as lysosomal storage disorders, pathogenic levels of a particular metabolite accumulate in the lysosome due to the loss of function of a human gene required for catabolism or transport of a substrate normally digested in the lysosome. In Neimann-Pick type C (NPC) disease, the lysosomal cholesterol exporter, NPC1, is inoperative, causing accumulation of cholesterol within lysosomes, resulting in disruption of lysosomal function, which is propagated to other organelles (e.g., mitochondria) also compromising their function. Ultimately, this damage leads to progressive neurodegeneration in patients. The accumulation of cholesterol caused by loss of NPC1 also chronically hyperactivates mTORC1, further interfering with the regulation of cellular homeostasis.To increase our understanding of the factors that cause lysosomal failure in NPC disease, I examined the compositional and functional alterations that occur in lysosomes lacking NPC1 activity. Likewise, I studied how NPC1 loss triggers aberrant mTORC1 signaling and how dysregulated mTORC1 contributes to organelle pathogenesis. I first used organelle immuno-isolation in conjunction with proteomic profiling to uncover a pronounced proteolytic impairment of NPC lysosomes that is compounded by depletion of luminal hydrolases and enhanced susceptibility tomembrane damage. I also tested a panel of NPC1 mutants in NPC1-deficient cells and demonstrated that, cholesterol transport by NPC1 is tightly linked to regulation of mTORC1 activity, indicating that lysosomal cholesterol accumulation is the primary underlying cause of mTORC1 hyperactivation in NPC disease. Next, I demonstrated that genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis and lysosomal membrane integrity without correcting cholesterol accumulation, implicating mTORC1 hyperactivity as a main driver of downstream pathogenesis, including the loss of mitochondrial quality control and function. In agreement with those conclusions, I showed that mTORC1 inhibition reverses lysosomal and mitochondrial dysfunction in a neuronal model of NPC, extending my findings to a disease-relevant cellular context. Thus, targeting the cholesterol-mTORC1 signaling pathway may represent a novel therapeutic avenue in NPC that could complement or replace current approaches.

ISBN: 9798691239229Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Cholesterol

The Role of Lysosomal Cholesterol Transport in Cellular Nutrient Sensing and Organelle Homeostasis.
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