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Quantitative proteome analysis of LAP1-deficient human fibroblasts reveals key signaling pathways deregulated in LAP1-associated diseases

ABSTRACT: Lamina-associated polypeptide 1 (LAP1), a ubiquitously expressed nuclear envelope protein, seems to be essential for the maintenance of cell homeostasis. Although rare, mutations in the human LAP1-encoding TOR1AIP1 gene have been associated to the development of many severe pathologies (e.g. dystonia, myasthenic syndrome, muscular dystrophy, cardiomyopathy and multisystemic syndrome), which can culminate in the premature death of affected individuals. Despite recent evidence of the pathogenicity of TOR1AIP1 genetic alterations, a knowledge gap still exists regarding the physiological roles of LAP1 and, therefore, additional investigation is required to fully understand its biological relevance. To this end, a quantitative proteome analysis of patient-derived skin fibroblasts carrying a pathological TOR1AIP1 mutation (LAP1 E482A), which had been linked to strongly reduced LAP1 protein levels, was carried out. Using the liquid chromatography with tandem mass spectrometry (LC–MS/MS) technology, 386 differentially expressed proteins were found in LAP1 E482A fibroblasts relative to control fibroblasts. A bioinformatic analysis of the LC–MS/MS-identified differentially expressed proteins revealed several biological processes misregulated as a result of human LAP1 deficiency, such as DNA repair, messenger RNA degradation, proteostasis, glutathione metabolism/response to oxidative stress, neuronal development and muscle contraction, among others. Besides shedding light on potential new LAP1’s functions, this work also provides valuable clues about key signaling pathways that may be targeted in disease-modifying therapies for LAP1-associated disorders.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: guadalupe espadas

LAB HEAD: Eduard Sabidó

PROVIDER: PXD035200 | Pride | 2024-06-27

REPOSITORIES: Pride

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			Action	DRS
	2021MQ043_CATI_001_01_2ug.raw	Raw
	2021MQ043_CATI_001to006.msf	Msf
	2021MQ043_CATI_002_01_2ug.raw	Raw
	2021MQ043_CATI_003_01_2ug.raw	Raw
	2021MQ043_CATI_004_01_2ug.raw	Raw

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Quantitative proteome analysis of LAP1-deficient human fibroblasts reveals key signaling pathways deregulated in LAP1-associated diseases

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