Mutations to the LMNA gene cause laminopathies including Hutchinson-Gilford progeria syndrome (HGPS) that severely affect the cardiovascular system. 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, where progeroid pathology is apparent, but a days-long lifetime in the liver and gastrointestinal tract, which are spared from disease. The A-type Lamins are insoluble and densely bundled in cardiovascular tissues, which may present an energetic barrier to degradation and promote long protein lifetime. Progerin is even more long-lived than Lamin A/C in the cardiovascular system and accumulates there over time. Progerin accumulation interferes broadly with protein homeostasis, as hundreds of abundant proteins turn over more slowly in progeroid tissues. These findings indicate that potential gene therapy interventions for HGPS will have significant latency and limited potency in disrupting the long-lived Progerin protein. Finally, we reveal that human disease alleles are significantly over-represented in the long-lived proteome, indicating that long protein lifetime may influence disease pathology and present a significant barrier to gene therapies for numerous human diseases.
Keywords: Biological Sciences; Cell Biology; nuclear lamina; progeria; protein homeostasis.