Our objectives are to understand the function of prelamin A and lamin C (alternatively spliced products of the LMNA gene) in health and disease, and to develop new strategies to treat prelamin A diseases, which include progeroid syndromes. In this application, we will explore a new therapeutic strategy for prelamin A diseases that was suggested by a new discovery in lamin A biology in the central nervous system. The classic progeroid syndrome of children, Hutchinson-Gilford progeria syndrome (HGPS), is caused by a mutant form of prelamin A. Affected children are healthy at birth but soon develop several disease phenotypes that resemble premature aging. For the past 9 years, we have worked to investigate the biology of nuclear lamins with an eye towards finding mechanism-based therapies for diseases of the nuclear lamina (laminopathies). This approach led us to propose, in 2004, that protein farnesylation might be important for the pathogenesis of prelamin A-related progeroid syndromes. Since then, we have tested inhibitors of protein farnesyltransferase (FTIs) in mouse models of progeria, which prompted an FTI clinical trial in children with HGPS. That trial has been completed, and it appeared that the FTI improved several disease phenotypes. However, it is very clear that FTI treatment falls far short of a cure, both in mouse models and in humans. Fresh therapeutic strategies are needed. We recently uncovered a novel feature of lamin A biology that suggested a pathway to a new treatment strategy for prelamin A diseases. We discovered that neurons express lamin C but very little prelamin A. This observation likely explains why children with HGPS are spared from neurodegenerative disease. More importantly, our observation led us to think seriously about new therapeutic strategies for progeria. Prelamin A synthesis is negligible in the brain, and the brain is spared from disease in HGPS. If we can identify strategies for reducing prelamin A levels in peripheral tissues (mirroring the situation in the brain), it might be possible to prevent-or even reverse-the disease phenotypes of HGPS and other prelamin A diseases. For the next 5 years, we will investigate mechanisms by which the brain regulates prelamin A synthesis. In addition, we will investigate the DNA sequences and proteins that regulate lamin C and prelamin A synthesis. We will also work to characterize antisense oligonucleotides that alter splicing and tip the balance towards lamin C production at the expense of prelamin A. Finally, we will determine if reducing prelamin A synthesis in peripheral tissues ameliorates disease phenotypes in a new mouse model of HGPS.

Public Health Relevance

Genetic defects that lead to an accumulation of mutant forms of prelamin A lead to premature aging disorders such as Hutchinson-Gilford progeria syndrome (HGPS). We recently discovered a new molecular mechanism that suppresses the production of prelamin A in the brain. Building on that discovery, we have pioneered a new treatment strategy for HGPS and other prelamin A-related progeroid disorders.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Guo, Max
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Kim, Paul H; Luu, Jennings; Heizer, Patrick et al. (2018) Disrupting the LINC complex in smooth muscle cells reduces aortic disease in a mouse model of Hutchinson-Gilford progeria syndrome. Sci Transl Med 10:
Chen, Natalie Y; Kim, Paul; Weston, Thomas A et al. (2018) Fibroblasts lacking nuclear lamins do not have nuclear blebs or protrusions but nevertheless have frequent nuclear membrane ruptures. Proc Natl Acad Sci U S A 115:10100-10105
Tu, Yiping; Sánchez-Iglesias, Sofía; Araújo-Vilar, David et al. (2016) LMNA missense mutations causing familial partial lipodystrophy do not lead to an accumulation of prelamin A. Nucleus 7:512-521
Lee, John M; Nobumori, Chika; Tu, Yiping et al. (2016) Modulation of LMNA splicing as a strategy to treat prelamin A diseases. J Clin Invest 126:1592-602
Lee, John M; Jung, Hea-Jin; Fong, Loren G et al. (2014) Do lamin B1 and lamin B2 have redundant functions? Nucleus 5:287-92
Lee, John M; Tu, Yiping; Tatar, Angelica et al. (2014) Reciprocal knock-in mice to investigate the functional redundancy of lamin B1 and lamin B2. Mol Biol Cell 25:1666-75
Jung, Hea-Jin; Tu, Yiping; Yang, Shao H et al. (2014) New Lmna knock-in mice provide a molecular mechanism for the 'segmental aging' in Hutchinson-Gilford progeria syndrome. Hum Mol Genet 23:1506-15