The proteins of the nuclear lamina have generated enormous interest because missense mutations in LMNA (the gene for prelamin A, which encodes both lamin A and lamin C) cause a host of diseases, including Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, Charcot-Marie-Tooth type II peripheral neuropathy, and Hutchinson-Gilford progeria syndrome. Prelamin A, the precursor to mature lamin A, undergoes a series of posttranslational modifications, including the covalent attachment of a lipid to the protein, proteolytic clipping of the protein, and methylation of the protein. These post-translational modifications are important both to the targeting of the lamins to the nuclear envelope and to their function. The laboratory of my mentor, Dr. Stephen G. Young, recently identified an endoprotease, Zmpste24, that is required for the maturation of prelamin A to lamin A. Interestingly, Zmpste24-deficient mice develop a muscle weakness phenotype I strikingly similar to that observed in mice lacking lamin A/C. A key objective of my application is to define the pathological and molecular underpinnings of the possible muscular dystrophy, peripheral neuropathy and progeria phenotype in Zmpste24-deficient mice, as well as compare them to mice harboring mutant Lmna alleles. Finally, I will investigate the consequences of defective posttranslational processing of lamin A on a cellular level in order to elucidate the biochemical role of Zmpste24 in prelamin A processing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AG024044-01
Application #
6738210
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Sierra, Felipe
Project Start
2004-03-16
Project End
2006-03-15
Budget Start
2004-03-16
Budget End
2005-03-15
Support Year
1
Fiscal Year
2003
Total Cost
$39,700
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158