At the nucleus of the problem: Nuclear proteins and disease

Nadir M. Maraldi, Giovanna Lattanzi, Stefano Squarzoni, Patrizia Sabatelli, Sandra Marmiroli, Andrea Ognibene, Francesco A. Manzoli

Research output: Contribution to journalArticle

Abstract

The full complexity of the cell nucleus has been only partly revealed. The main problem to solve resides in the paradox that nuclear functions require the highest degree of organization despite the absence of intranuclear membrane-delimited compartments. However, the presence in the nucleus of discrete domains is attested by the finding that many nuclear components participating in related pathways are concentrated in specific areas, leading to the concept of a functional compartmentalization of the nucleus. The organization of nuclear functions occurs at multiple levels. The nuclear import of transcription factors (TFs) and the presence of a modular organization of flanking regulatory elements in the genome is necessary but insufficient to support expression in a biological context. In fact, the structural linkages between gene organization and components of the transcriptional control are provided by the chromatin arrangement, which depends on its interaction with the non-chromatin components of the nucleus, defined nucleoskeleton or nuclear matrix. The importance of this organization is revealed by the mis-localization of nuclear proteins in cancer, neurodegenerative, and genetic disease. In some leukemias the intranuclear distribution of TFs, normally linked to the nuclear matrix at specific sites, is altered. Analogous alterations have been identified in some neurodegenerative diseases, like cerebellar ataxia, in which the changes in distribution of functional proteins within the nucleus are determined by an altered organization of the nuclear matrix. The mechanisms connecting alterations of the nuclear morphology to pathogenetic processes are very complex, because they did not directly affect cell functions related to the pathology, but basic processes, such as the control of gene expression. In recent years, a group of human genetic diseases has been demonstrated to be due to the altered expression of proteins localized at the nuclear envelope; thus they were defined nuclear envelopathies. The first pathology to be identified was the Emery-Dreifuss muscular dystrophy (EDMD) due, in its X-linked form, to the absence of emerin, a protein associated with the inner nuclear membrane, and, in its autosomic form, to the altered expression of lamin A/C. Thereafter, other muscular dystrophies and some syndromes affecting the adipose or nerve tissues have been identified as due to mutations of the LMNA gene coding for lamin A/C, one of the main components of the nuclear lamina. These diseases have been thus named laminopathies. The pathophysiology of these diseases has been widely investigated because it appears to be essential to understand some basic mechanisms. In fact, the lack or altered expression of proteins of the nuclear lamina or of the inner nuclear membrane that occurs in each cell type, but results in functional alterations in specific tissues in the different laminopathies (skeletal, cardiac, adipose, nervous tissue), might necessarily affect gene expression. During differentiation, gene silencing by heterochromatization is modulated through chromatin remodeling and TF binding to the nuclear matrix that induce gene transactivation. We obtained experimental evidence of specific alterations of the peripheral heterochromatin and of the adjacent nuclear lamina in both X-linked and autosomic variants of Emery-Dreifuss muscular dystrophy. Chromatin arrangement is modulated by multi-protein chromatin remodeling complexes (CRCs) that include nuclear β-actin and actin-binding proteins, localized at the nuclear matrix. The CRCs are activated by inositides, whose nuclear metabolism has been demonstrated to depend on specific phospholipase C isoforms and lipid kinases. Since both emerin and lamin A/C have been demonstrated to interact with β-actin, it is conceivable that the altered expression of the nuclear envelope-associated proteins that occurs in EDMD could induce changes in the chromatin arrangement that result in a modified gene expression. This might impair cell differentiation during myogenesis as well as muscle regeneration by satellite cells in damaged muscle fibers.

Original languageEnglish
Pages (from-to)411-443
Number of pages33
JournalAdvances in Enzyme Regulation
Volume43
DOIs
Publication statusPublished - 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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