Presenilins and γ-Secretase in Membrane Proteostasis

Topic: Disease mechanisms in lab and animal studies

The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein (APP) and the generation of amyloid β-protein (Aβ). The two homologous proteins PS1 and PS2 represent the catalytic subunits of distinct γ-secretase complexes that mediate a variety of cellular processes, including membrane protein metabolism, signal transduction, and cell differentiation. While the intramembrane cleavage of select proteins by γ-secretase is critical in the regulation of intracellular signaling pathways, the plethora of identified protein substrates could also indicate an important role of these enzyme complexes in membrane protein homeostasis. In line with this notion, PS proteins and/or γ-secretase has also been implicated in autophagy, a fundamental process for the maintenance of cellular functions and homeostasis. Dysfunction in the clearance of proteins in the lysosome and during autophagy has been shown to contribute to neurodegeneration. This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy.

@article{oikawa2019-30823664,
  author  = {Oikawa, Naoto and Walter, Jochen},
  title   = {{Presenilins and γ-Secretase in Membrane Proteostasis}},
  journal = {Cells},
  year    = {2019},
  doi     = {10.3390/cells8030209},
  pmid    = {30823664},
  url     = {https://doi.org/10.3390/cells8030209}
}

Key findings

• The two homologous proteins PS1 and PS2 represent the catalytic subunits of distinct γ-secretase complexes that mediate a variety of cellular processes, including membrane protein metabolism, signal transduction, and cell differentiation.
• While the intramembrane cleavage of select proteins by γ-secretase is critical in the regulation of intracellular signaling pathways, the plethora of identified protein substrates could also indicate an important role of these enzyme complexes in membrane protein homeostasis.
• In line with this notion, PS proteins and/or γ-secretase has also been implicated in autophagy, a fundamental process for the maintenance of cellular functions and homeostasis.
• Dysfunction in the clearance of proteins in the lysosome and during autophagy has been shown to contribute to neurodegeneration.
• This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3390/cells8030209
• PubMed: 30823664
• Original source →

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Also tagged “autophagy”

240 studies in the library carry the topic tag “autophagy”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 240 tagged studies.

• The importance of sequence diversity in the aggregation and evolution of proteins Nature · 2005-12-01 · usefulness score 41/100 · Prevention trials
• Development of LNA Gapmer Oligonucleotide-Based Therapy for ALS/FTD Caused by the C9orf72 Repeat Expansion Methods in molecular biology (Clifton, N.J.) · 2020 · usefulness score 39/100 · Drug development
• Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations Cell · 2010-06-10 · usefulness score 36/100 · Risk genes beyond APOE

Similar studies

• Presenilin 1 Regulates Membrane Homeostatic Pathways that are Dysregulated in Alzheimer's Disease 2020 · Risk genes beyond APOE
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• Mechanisms of neurodegeneration - Insights from familial Alzheimer's disease 2020 · Risk genes beyond APOE
• When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease 2007 · Biomarkers

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