Selected as the cover story of EMBO Reports on the issue of October 5th, the study led by Chair Professor Hong-Chen Chen at National Yang-Ming University in collaboration with Dr. Ya-Hui Chi at National Health Research Institutes, Taiwan, uncovers the pathogenesis of progeria may result from the malfunction of primary cilia. This finding provides with putative therapeutic strategies for progeria diseases.
The patients with Hutchinson-Gilford progeria syndrome (HGPS) appear premature symptoms in their infancy with an average life span of 13 years. The clinical phenotypes are characterized by severe growth retardation, loss of subcutaneous fat, wrinkled skin, hair loss, osteoporosis, joint stiffness, and cardiovascular diseases. Despite being described in 1886, HGPS was not attributed to mutations in the LMNA gene until 2003. However, until now the underlying pathogenesis of HGPS remains unclear. The LMNA gene produces lamin A, a major component of the nucleoskeleton called nuclear lamina. Once LMNA gene mutated, the nucleus becomes wrinkled and even undergo severe deformation. Aside from HGPS, LMAN gene mutations have been attributed to at least 10 human diseases, such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and so on. These diseases are collectively called laminopathies.
The research team led by Professor Hong-Chen Chen found for the first time that HGPS patients-derived skin fibroblasts show fewer and shorter primary cilia. Since the primary cilium functions like a cellular antenna that detects changes in the extracellular environments and transduces signals to the cell interior to respond those changes, it is possible that the malfunction of primary cilia may be a cause for HGPS. Therefore, the team further examined Lmna null mice, and proved that primary cilia were defective in many organs of this prematurely aged, lamin A-deficient mice. Subsequently, the researchers reduced lamin A-expression in human retinal pigment epithelial cells with a shRNA-interference technique and found this manipulation led to abnormal primary cilia in these cells. For the mechanistic study, the research team found that lamin A deficiency led to excessive assembly of the actin cytoskeleton, therefore hampering the formation of primary cilia. On the contrary, disruption of the actin filaments significantly rescued cilia formation in lamin A-deficient cells. This discovery not only provides new insights for the pathogenesis of progeria syndrome, but also shed light on new therapeutic strategies for related diseases.
This study was supported by the Ministry of Science and Technology, Taiwan, and performed mainly by postdoctoral fellow Jia-Rong Fan (first author of this paper) in the laboratory of Professor Chen. The HGPS fibroblasts and Lmna null mice were provided by Associated Researcher Dr. Ya-Hui Chi of National Health Research Institutes, Taiwan. The immunohistochemistry of Lmna null mice and the observation of primary cilia were instructed by Professor Li-Ru You and Associated Professor Won-Jing Wang of the Institute of Biochemistry and Molecular Biology, National Yang-Ming University.
Lamin A, a major component of the nuclear lamina, regulates ciliogenesis through maintaining actin homeostasis. These findings indicate that defects in primary cilia may be involved in the pathogenesis of laminopathies, such as Hutchinson-Gilford progeria syndrome.