Laminopathies and the long strange trip from basic cell biology to therapy
Howard J. Worman, Loren G. Fong, Antoine Muchir, Stephen G. Young
Howard J. Worman, Loren G. Fong, Antoine Muchir, Stephen G. Young
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Laminopathies and the long strange trip from basic cell biology to therapy

Abstract

The main function of the nuclear lamina, an intermediate filament meshwork lying primarily beneath the inner nuclear membrane, is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organization, connecting the nucleus to the cytoplasm, gene transcription, and mitosis. In somatic cells, the main protein constituents of the nuclear lamina are lamins A, C, B1, and B2. Interest in the nuclear lamins increased dramatically in recent years with the realization that mutations in LMNA, the gene encoding lamins A and C, cause a panoply of human diseases (“laminopathies”), including muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. Here, we review the laminopathies and the long strange trip from basic cell biology to therapeutic approaches for these diseases.

Authors

Howard J. Worman, Loren G. Fong, Antoine Muchir, Stephen G. Young

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Figure 3

Studies from LmnaH222P/H222P knockin mice and Emd-knockout mice suggest that activation of ERK and/or JNK underlies the development of cardiomyopathy.

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Studies from LmnaH222P/H222P knockin mice and Emd-knockout mice suggest ...
Cardiomyocytes in normal hearts of wild-type mice exhibit detectable ERK and JNK activation, as judged by low levels of expression of downstream transcription factors such as Elk1, Elk4, Aft2, and Aft4 (left panel). Both ERK and JNK signaling are increased in hearts from mice harboring the H222P point mutation in Lmna, whereas ERK is activated in hearts of Emd-knockout mice (red arrows; middle panel). Phosphorylation and nuclear translocation of ERK and JNK modulate gene expression, leading to dilated cardiomyopathy (middle panel). Currently, it is unclear how alterations in A-type lamins or the loss of emerin lead to the activation of ERK and/or JNK. Studies in LmnaH222P/H222P mice have shown that pharmacological inhibition of MEK, the kinase that phosphorylates ERK, can prevent the development of cardiomyopathy at 16 weeks of age (right panel).