Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.02.04.527139v1?rss=1

Authors: Hasper, J., Welle, K., Swovick, K., Hryhorenko, J., Ghaemmaghami, S., Buchwalter, A.

Abstract:
Mutations to the LMNA gene cause laminopathies including Hutchinson-Gilford progeria syndrome (HGPS). The origins of tissue specificity in these diseases are unclear, as the A-type Lamins are abundant and broadly expressed proteins. We show that A-type Lamin protein and transcript levels are uncorrelated across tissues. As protein-transcript discordance can be caused by variations in protein lifetime, we applied quantitative proteomics to profile protein turnover rates in healthy and progeroid tissues. We discover that tissue context and disease mutation each influence A-type Lamin protein lifetime. Lamin A/C has a weeks-long lifetime in the aorta, heart, and fat, but a days-long lifetime in tissues spared from disease. Progerin is even more long-lived than Lamin A/C in the cardiovascular system and accumulates there over time. These proteins are insoluble and densely bundled in cardiovascular tissues, which may present an energetic barrier to degradation. We reveal that human disease alleles are significantly over-represented in the long-lived proteome. These findings indicate that gene therapy interventions will have significant latency and limited potency in disrupting long-lived disease-linked proteins such as Progerin.

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