The farnesylated nuclear proteins KUGELKERN and LAMIN B promote aging-like phenotypes in Drosophila flies.
The nuclear lamina consists of a meshwork of lamins and lamina-associated proteins, which provide mechanical support, control size and shape of the nucleus, and mediate the attachment of chromatin to the nuclear envelope. Abnormal nuclear shapes are observed in aging cells of humans and nematode worms. The expression of laminDelta50, a constitutively active lamin A splicing variant in Hutchinson-Gilford progeria syndrome patients, leads to the lobulation of the nuclear envelope accompanied by DNA damage, and loss of heterochromatin. So far, it has been unclear whether these age-related changes are laminDelta50 specific or whether proteins that affect nuclear shape such as KUGELKERN or LAMIN B in general play a causative role in senescence. Here we show that in adult Drosophila flies, the size of the nuclei increases with age and the nuclei assume an aberrant shape. Moreover, induced expression of the farnesylated lamina proteins Lamin B and Kugelkern cause aberrant nuclear shapes and reduce the lifespan of adult flies. The shorter lifespan correlates with an early decline in age-dependent locomotor behaviour. Expression of kugelkern or lamin B in mammalian cells induces a nuclear lobulation phenotype in conjunction with DNA damage, and changes in histone modification similar to that found in cells expressing laminDelta50 or in cells from aged individuals. We conclude that lobulation of the nuclear membrane induced by the insertion of farnesylated lamina-proteins can lead to aging-like phenotypes.
Brandt
Annely
A
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany. a.brandt@zmbh.uni-heidelberg.de
Krohne
Georg
G
Grosshans
Jörg
J
D000375:Aging / Q000502:physiology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D048430:Cell Shape; D004249:DNA Damage; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D005347:Fibroblasts / Q000166:cytology; D020868:Gene Silencing; D034921:Lamin Type B / Q000378:metabolism*; D008136:Longevity; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D017368:Protein Prenylation
D029721:Drosophila Proteins; D034921:Lamin Type B; D009687:Nuclear Proteins; C511714:kuk protein, Drosophila