Lamin proteins assemble a complex protein meshwork known as the nuclear lamina of the inner nuclear membrane. Besides their structural role, lamins are essential in multiple cellular functions, such as DNA replication, chromatin organization, gene regulation, and cell differentiation. Mutations in the human LMNA gene encoding for Lamin A/C can result in a diverse set of genetic disorders known as laminopathies. Examples comprise Emery-Dreifuss muscular dystrophy (EDMD) characterized by muscle wasting or Hutchinson-Gilford progeria syndrome (HGPS) causing a severe form of premature ageing. To genetically dissect the pathogenic mechanisms of human laminopathies, we introduced the corresponding mutations of patients from our clinic into the lamin gene
lmn-1 of C. elegans. To recapitulate the muscle disorders observed in the patients, the mutated
lmn-1 forms were specifically expressed in the body wall muscle cells. The previously described EDMD-causing Y59C (Mattout et al., 2012) was employed as a positive control. Motility assays based on swimming revealed that lamin mutations impair the motility of transgenic worms. Immunostaining for muscle proteins detected structural defects in the internal Myosin and Actin filaments as well as in the attachment structures based on Myotactin and Perlecan proteins. Currently, we are also examining worms with expression of lamin mutations in other tissues such as the intestine. The NuRD (Nucleosome Remodeling and Deacetylase) complex has been implicated in HGPS (Pegoraro et al., 2009). Particularly, the histone chaperone RBBP4 (LIN-53 in C. elegans), a core subunit of NuRD, was identified to be an interactor of Lamin A. Moreover, loss of RBBP4 correlates with global ageing-related chromatin defects in both HGPS and normally aged cells. Notably, depletion of the RBBP4 homolog LIN-53 by RNAi or mutation in worms leads to muscle dysfunction and lifespan shortening. Currently, we are testing whether the expression level and cellular localization of LIN-53, as well as histone modifications, are affected in the patient-derived lamin mutants in order to assess the crosstalk between Lamin and LIN-53 in the development of laminopathies.