Long lifetime and tissue-specific accumulation of lamin A/C in Hutchinson-Gilford progeria syndrome.

Abstract

LMNA mutations cause laminopathies that afflict the cardiovascular system and include Hutchinson-Gilford progeria syndrome. The origins of tissue specificity in these diseases are unclear as the lamin A/C proteins are broadly expressed. We show that LMNA transcript levels are not predictive of lamin A/C protein levels across tissues and use quantitative proteomics to discover that tissue context and disease mutation each influence lamin A/C protein's lifetime. Lamin A/C's lifetime is an order of magnitude longer in the aorta, heart, and fat, where laminopathy pathology is apparent, than in the liver and intestine, which are spared from the disease. Lamin A/C is especially insoluble in cardiovascular tissues, which may limit degradation and promote protein stability. Progerin is even more long lived than lamin A/C in the cardiovascular system and accumulates there over time. Progerin accumulation is associated with impaired turnover of hundreds of abundant proteins in progeroid tissues. These findings identify impaired lamin A/C protein turnover as a novel feature of laminopathy syndromes.

• Authors: John Hasper, Kevin Welle, Kyle Swovick, Jennifer Hryhorenko, Sina Ghaemmaghami, Abigail Buchwalter
• Journal: The Journal of cell biology (J Cell Biol) Vol. 223 Issue 1 (01 01 2024) ISSN: 1540-8140 [Electronic] United States
• PMID: 37966721 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2023 Hasper et al.

Chemical References

• Lamin Type A

Topics

• Humans
• Lamin Type A (genetics, metabolism)
• Mutation
• Progeria (genetics, pathology)
• Proteomics