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The γ-secretase substrate proteome and its role in cell signaling regulation

ABSTRACT: γ-Secretase is involved in the regulated intramembrane proteolysis (RIP) of a variety of integral membrane proteins and generates the amyloid peptide (Aβ) in Alzheimer’s Disease (AD). Microglia are centrally involved in AD, but the substrates and function of γ-secretase in these cells remain largely unstudied. Using a novel γ-Secretase Substrate Identification (G-SECSI) method, we identified 85 substrates, of which 59 were previously unknown, in stem cell derived microglia-like cells. More than 60% of those are signalling receptors possibly involved in cell state regulation. Inhibition of γ-secretase using Semagacestat or selective genetic knockout alters the expression of homeostatic (HM) and disease-associated (DAM) genes, in particular when microglia are exposed to amyloid plaques in vivo. Thus, γ-secretase regulates tonic signaling via a spectrum of substrates in microglia in steady state, and its blockage results in the defective transition to the DAM response in AD.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Andrew Howden

LAB HEAD: Bart De

PROVIDER: PXD039238 | Pride | 2023-11-14

REPOSITORIES: Pride

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			Action	DRS
	AH-D-1-10.raw	Raw
	AH-D-1-11.raw	Raw
	AH-D-1-12.raw	Raw
	AH-D-1-13.raw	Raw
	AH-D-1-2.raw	Raw

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