2. Academic Validation
  3. Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function

Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function

  • Int J Mol Sci. 2024 May 16;25(10):5417. doi: 10.3390/ijms25105417.
Marietta Fabiano 1 2,  Naoto Oikawa 1,  Anja Kerksiek 3,  Jun-Ichi Furukawa 4 5,  Hirokazu Yagi 6 7,  Koichi Kato 6 7 8,  Ulrich Schweizer 2,  Wim Annaert 9 10,  Jongkyun Kang 11,  Jie Shen 11 12,  Dieter Lütjohann 3,  Jochen Walter 1
Affiliations

Affiliations

  • 1 Department of Neurology, Universitätsklinikum Bonn, 53127 Bonn, Germany.
  • 2 Institut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany.
  • 3 Institute of Clinical Chemistry and Clinical Pharmacology, Universitätsklinikum Bonn, 53127 Bonn, Germany.
  • 4 Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
  • 5 Division of Glyco-Systems Biology, Institute for Glyco-Core Research, Tokai National Higher Education and Research System, Nagoya 466-8550, Japan.
  • 6 Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
  • 7 Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
  • 8 Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki 444-8585, Japan.
  • 9 Laboratory for Membrane Trafficking, VIB-Center for Brain and Disease Research, KU Leuven, 3000 Leuven, Belgium.
  • 10 Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium.
  • 11 Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 12 Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
PMID: 38791456 DOI: 10.3390/ijms25105417
Abstract

Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the pathogenesis of Alzheimer disease (AD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular Cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to Cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in the lysosomes of embryonic fibroblasts from Psen1-knockout (PS1-KO) and Psen2-KO (PS2-KO) mice and was associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular Cholesterol transport in late endosomal/lysosomal compartments. Mass spectrometry and complementary biochemical analyses also revealed abnormal N-glycosylation of NPC1 and several Other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular Cholesterol accumulation prominently in lysosomes and decreased NPC1, thereby resembling the changes in PS1-KO and PS2-KO cells. In turn, treatment of PS1-KO and PS2-KO mouse embryonic fibroblasts (MEFs) with the chaperone inducer arimoclomol partially normalized NPC1 expression and rescued lysosomal Cholesterol accumulation. Additionally, the intracellular Cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by overexpression of NPC1. Collectively, these data indicate that a loss of PS function results in impaired protein N-glycosylation, which eventually causes decreased expression of NPC1 and intracellular Cholesterol accumulation. This mechanism could contribute to the neurodegeneration observed in PS KO mice and potentially to the pathogenesis of AD.

Keywords

N-glycosylation; NPC1; Presenilin; cholesterol; lysosome.

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