The most common cause of Hutchison-Gilford Progeria Syndrome (HOPS) is a de novo point mutation in LMNA, the gene encoding lamin A, that activates a cryptic splice site that produces a mutant lamin A that is missing 50 amino acids in its tail domain, called (delta)50 lamin A. This deletion includes a cleavage site that normally releases the lamin A protein from the nuclear membrane after localization and appears to enhance the association with the inner nuclear membrane. Expression of (delta)50 lamin A interferes with many fundamental cellular processes and produces abnormal nuclear morphology and mechanical properties that gives rise to signs of aging. This same mechanism has been implicated in physiological aging and is reminiscent of other pathologies that result from destructive protein-membrane interactions, such as Alzheimer's disease, tauopathies and prion diseases. In this project, we will determine whether the strong interaction between (delta)50 lamin A and the inner nuclear membrane can be attributed to an enhanced protein-membrane interaction and decipher the physiochemical mechanism responsible for the amplified response of (delta)50 lamin A's affinity for the inner nuclear membrane. The hypotheses underlying the mechanisms causing this enhanced interaction will be tested in vitro using model membrane systems and various mutants of (delta)50 lamin A.

Public Health Relevance

Destructive protein-membrane interactions are common to many advanced age-related pathologies, including Alzheimer's disease, Parkinson's disease other tauopathies and prion diseases, as well as physiological aging. However, little is understood about the interactions that occur at membrane interfaces. This goal of this project is to understand a protein-membrane disturbance that characterizes a premature aging syndrome, Hutchinson-Gilford Progeria Syndrome, and contributes to physiological aging, which could lead to further understanding of other toxic protein-membrane interactions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F04B-L (20))
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Velazquez, Jose M
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University of Pittsburgh
Schools of Medicine
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Kalinowski, Agnieszka; Yaron, Peter N; Qin, Zhao et al. (2014) Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson-Gilford progeria syndrome. Biophys Chem 195:43-8
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