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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AG030905-05
Application #
8265272
Study Section
Special Emphasis Panel (ZRG1-F04B-L (20))
Program Officer
Velazquez, Jose M
Project Start
2009-07-01
Project End
2013-05-31
Budget Start
2012-07-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$45,396
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Kalinowski, Agnieszka; Qin, Zhao; Coffey, Kelli et al. (2013) Calcium causes a conformational change in lamin A tail domain that promotes farnesyl-mediated membrane association. Biophys J 104:2246-53
Dahl, Kris Noel; Kalinowski, Agnieszka (2011) Nucleoskeleton mechanics at a glance. J Cell Sci 124:675-8
Qin, Zhao; Kalinowski, Agnieszka; Dahl, Kris Noel et al. (2011) Structure and stability of the lamin A tail domain and HGPS mutant. J Struct Biol 175:425-33
Dahl, Kris Noel; Kalinowski, Agnieszka; Pekkan, Kerem (2010) Mechanobiology and the microcirculation: cellular, nuclear and fluid mechanics. Microcirculation 17:179-91