Role of gamma-secretase in cellular cholesterol metabolism
Final Report Abstract
Cholesterol is one of the essential components of a cell and involves in a variety of cellular functions including membrane trafficking and transmembrane signaling. Disturbance of cellular cholesterol metabolism, particularly intracellular cholesterol accumulation, results in neurodegeneration as seen in a hereditary brain disease: Niemann-Pick disease type C, indicating an importance of strict regulation of cellular cholesterol metabolism. Disturbed cholesterol metabolism is considered to contribute to the pathogenesis of Alzheimer disease (AD). In this pathological process, dysfunction of a membrane protease, γ-secretase, is significantly involved. However, molecular mechanism of how γ-secretase dysfunction results in disturbance of cellular cholesterol metabolism is still not fully clarified. In this project, we tried to identify and characterize the molecular mechanisms underlying abnormal cellular cholesterol metabolism upon AD-related γ-secretase dysfunction. First, we tried to clarify which molecule is critically involved in cellular cholesterol accumulation upon γ-secretase dysfunction and found that disturbance of intracellular cholesterol transport due to decrease of a cholesterol transporter, NPC1, can be a cause of cellular cholesterol accumulation in neurons. Glycosylation impairment in membrane proteins including NPC1 was also detected in γ-secretase deficient cells, suggesting promoted degradation of unfolded NPC1 can be a potential mechanism of NPC1 decrease upon γ-secretase dysfunction. In terms of relevance of NPC1 decrease to AD pathogenesis, decreases of NPC1 as well as presenilins (PSs), which are catalytic subunits of γsecretase, were unexpectedly detected in AD patient cells, including iPS cell-derived neurons, harboring an AD-related clinical APP mutation. Further analysis of the patient cells suggested potential contribution of decreased expression of a γ-secretase substrate for alteration of PSs and NPC1 expressions by the APP mutation. On the other hand, regarding the effect of AD-related clinical mutations on metabolism of γ-secretase substrates, significant increase of other γsecretase substrate, which is a glycosylated protein, was detected in all examined AD patient cells harboring clinical PS mutations, suggesting that clinical AD-related mutations differently affect cellular metabolism of γ-secretase substrates as well as glycosylated membrane proteins, which can eventually result in a disturbance of cellular cholesterol metabolism. By this project, a novel potential pathological pathway has been clarified; that is, γsecretase dysfunction results in glycosylation impairment, which, in turn, decreases NPC1 expression/function and leads to cellular cholesterol accumulation. Additionally, it has been also revealed that AD-related clinical mutations affect expression and function of γ-secretase components, it’s substrates, and NPC1, suggesting again the significant involvement of abnormal cholesterol metabolism in AD pathogenesis. Disturbance of cellular cholesterol metabolism has been indicated not only in neurons but also in glial cells. However, it remains unknown whether and how dysfunction of γ-secretase and NPC1 affect neural cholesterol metabolism and contributes to AD pathogenesis. Therefore, further analysis of consequences of γ-secretase and NPC1 dysfunction in neural cells as well as in brain is required in future.
Publications
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Presenilins and γ-Secretase in Membrane Proteostasis. Cells, 8(3), 209.
Oikawa, Naoto & Walter, Jochen
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Importance of γ-secretase in the regulation of liver X receptor and cellular lipid metabolism. Life Science Alliance, 3(6), e201900521.
Gutierrez, Esteban; Lütjohann, Dieter; Kerksiek, Anja; Fabiano, Marietta; Oikawa, Naoto; Kuerschner, Lars; Thiele, Christoph & Walter, Jochen
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Carboxy-terminal fragment of amyloid precursor protein mediates lipid droplet accumulation upon γ-secretase inhibition. Biochemical and Biophysical Research Communications, 570, 137-142.
Oikawa, Naoto; Fabiano, Marietta; Müller, Ulrike C. & Walter, Jochen
