Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

Alice-Anaïs Varlet,Catherine Badens,Emmanuèle Helfer

doi:10.3390/cells9091947

Abstract

Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the LMNA gene, with at least 20 mutations that are considered pathogenic. LMNA encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.

Highlights

In eukaryotic cells, the lamina, localized underneath the inner membrane of the nuclear envelope (NE), corresponds to a meshwork of type V intermediate filaments, called lamin proteins, and connects to lamin-associated proteins, such as the linker of nucleoskeleton and cytoskeleton (LINC) complex constituents and the nuclear pore complexes [1]
Both signaling pathways induce osteoblastogenesis and block the induction of peroxisome proliferator-activated endothelial differentiation, this study suggested that lamin A/C rewires the fate of several lineages, receptor-γ (PPAR-γ), which is a prime inducer of adipocytic differentiation
metabolic dysfunctions (MDs) associated with LMNA mutations represent complex conditions from the conclusion, associated levels

Summary

Introduction

The lamina, localized underneath the inner membrane of the nuclear envelope (NE), corresponds to a meshwork of type V intermediate filaments, called lamin proteins, and connects to lamin-associated proteins, such as the linker of nucleoskeleton and cytoskeleton (LINC) complex constituents and the nuclear pore complexes [1]. This model highlighted that the expression of the lamin A/C mutant led to a repositioning of the mesodermal regulator T/Brachyury locus toward the nuclear center, suggesting an enhanced activation propensity of the locus When addressing this issue, the authors reported phenotypic and transcriptional alterations in the mesodermal and endothelial differentiation of induced pluripotent stem cells generated from a patient with FPLD2 associated with the LMNA p.R482W mutation. By connecting a lipodystrophic LMNA mutation to a disruption of early mesodermal gene expression and defective endothelial differentiation, this study suggested that lamin A/C rewires the fate of several lineages, resulting, when mutated, in multi-tissue pathogenic phenotypes These studies suggest that prelamin A accumulation drives the premature senescence of stem cells, which could constitute the primary cause of MD and cardiovascular disease development in FPLD2 and in laminopathies in general (Figure 1).

Can the Biology of Adipose Tissue Explain the Physiopathology of FPLD2?

Conclusions

Cellular and molecular hallmarks of metabolic disorders associated

Familial Partial Lipodystrophy

Findings

Methods