Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice

• Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste24(-/-)) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste24(-/-) mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste24(-/-) mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste24(-/-) mice with half-normal levels of prelamin A (Zmpste24(-/-) mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, we bred and analyzed Zmpste24(-/-)Lmna(+/-) mice. As expected, prelamin A levels in Zmpste24(-/-)Lmna(+/-) cells were significantly reduced. Zmpste24(-/-)Lmna(+/-) mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste24(-/-)Lmna(+/-) cells than in Zmpste24(-/-) cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

CAAX proteiner

prelamin A

lamin A

djurmodeller

genteknik

Alleles

Animals

Blotting

Western

Cell Nucleus/metabolism

Cell Proliferation

Cells

Cultured

Dyes/pharmacology

Female

Fibroblasts/metabolism

Fluorescent Dyes/pharmacology

*Heterozygote

Humans

Lamins/*genetics

Lasers

Lipoproteins/*genetics

Membrane Proteins/*genetics

Metalloendopeptidases/*genetics

Metalloproteases/*genetics

Mice

Mice

Knockout

Mice

Transgenic

Microscopy

Fluorescence

Muscles/pathology

Nuclear Proteins/metabolism

Phenotype

Progeria/*genetics/pathology

Protein Precursors/metabolism

Research Support

Non-U.S. Gov't

Research Support

U.S. Gov't

P.H.S.

Skull/abnormalities/pathology

Time Factors

Tomography

X-Ray Computed

Publikations- och innehållstyp

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