Charcot-Marie-Tooth disease: emerging mechanisms and therapies

Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system. The disease is characterized by a progressive muscle weakness and atrophy, sensory loss, foot (and hand) deformities and steppage gait. While many of the genes associated with axonal CMT have been identified, to date it is unknown which mechanism(s) causes the disease. However, genetic findings indicate that the underlying mechanisms mainly converge to the axonal cytoskeleton. In this review, we will summarize the evidence for this pathogenic convergence. Furthermore, recent work with new transgenic mouse models has led to the identification of histone deacetylase 6 as a potential therapeutic target for inherited peripheral neuropathies. This enzyme deacetylates microtubules and plays a crucial role in the regulation of axonal transport. These findings offer new perspectives for a potential therapy to treat axonal Charcot-Marie-Tooth disease and other neurodegenerative disorders characterized by axonal transport defects.     

Translational control of gene expression and disease

In the past decade, translational control has been shown to be crucial in the regulation of gene expression. Research in this field has progressed rapidly, revealing new control mechanisms and adding constantly to the list of translationally regulated genes. There is accumulating evidence that translational control plays a primary role in cell-cycle progression and cell differentiation, as well as in the induction of specific cellular functions. Recently, the aetiologies of several human diseases have been linked with mutations in genes of the translational control machinery, highlighting the significance of this regulatory mechanism. In addition, deregulation of translation is associated with a wide range of cancers. Current research focuses on novel therapeutic strategies that target translational control, a promising concept in the treatment of human diseases.     

Synaptic dysfunction and oxidative stress in Alzheimer's disease: emerging mechanisms

In this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.     

Pretranslational control of Menkes disease gene expression

The gene for Menkes disease codes for a Cu-transporting ATPase that regulates Cu homeostasis in all tissues with the exception of adult liver. The basis for developmental or tissue-specific regulation at present is not understood. To learn if the regulation is associated with the promoter, we cloned and sequenced a 2.2 kb genomic DNA fragment flanking exon 1. When ligated into a pGL2 luciferase reporter gene construct, the 2.2 kb showed promoter activity, but not nearly to the extent of a 1.3 kb fragment previously reporter by Levinson et al. Sequence analysis of the nucleotides spanning the region between 1.3 kb and 2.2 kb revealed a 13-nucleotide motif ACACAAAAAAATA 2059 bp upstream from the start site that duplicated the `hunchback' binding site, a key site controlling developmental gene expression in Drosophila. Eliminating 129 bp containing the hunchback site (Hb) from the 5 end of the 2.2 kb stimulated promoter activity, suggesting the Hb site was basically suppressive. When ligated upstream of an SV40 and tested in SY5Y cells, however, the SV40 promoter activity was strongly stimulated, which conflicts with the site being suppressive. Mutating the site in the 2.2 kb weakened the promoter activity in SY5Y and HepG2 cells and a fragment with mutated sequence ligated upstream of the SV40 cancelled the activation of SV40 promoter activity. All data suggested the Hb site was a positive controlling site for Cu-ATPase expression. Nuclear extracts from SY5Y and HepG2 cells were observed to bind to a 106 bp probe with the Hb site in a gel-shift assay. Only SY5Y proteins, however, showed a slower moving shift band indicative of a secondary interaction. A probe with mutated sequences displayed the same shift pattern, suggesting other sites in the 106 bp DNA strand were also recognizing the nuclear proteins. A Southwestern analysis suggested that proteins of 125 kD, 70 kD, 50 kD and 42 kD bound to the wild type probe; a 60 kD and all with the exception of the 42 kD bound to the mutant probe. The data support the conclusion that the distal promoter of the Menkes disease gene contains elements that interact in combinatorial fashion to regulate Cu-ATPase expression and that tissue specificity may lie with the quantity or types of distinct DNA binding proteins in the nucleus.     

The TIM gene family: emerging roles in immunity and disease

The search for cell-surface markers that can distinguish T helper 1 (T(H)1) cells from T(H)2 cells has led to the identification of a new gene family, encoding the T-cell immunoglobulin mucin (TIM) proteins, some of which are differentially expressed by T(H)1 and T(H)2 cells. The role of the TIM-family proteins in immune regulation is just beginning to emerge. Here, we describe the various TIM-family members in mice and humans, and discuss the genetic and functional evidence for their role in regulating autoimmune and allergic diseases.     

Coal mining meets chromatin research: Digging for mechanisms in epigenetic control of gene expression

Editor's suggested further reading in BioEssays Epigenetics meets mathematics: Towards a quantitative understanding of chromatin biology Abstract     

Stochastic gene expression, disruption of tissue averaging effects and cancer as a disease of development

Despite the extensive literature describing the somatic genetic alterations in cancer cells, the precise origins of cancer cells remain controversial. In this article, I suggest that the etiology of cancer and the generation of genetic instability in cancer cells should be considered in the light of recent findings on both the stochastic nature of gene expression and its regulation at tissue level. By postulating that gene expression is intrinsically probabilistic and that stabilization of gene expression arises by cellular interactions in "morphogenetic fields", development and cellular differentiation can be rethought in an evolutionary perspective. In particular, this article proposes that disruptions of cellular interactions are the initial source of abnormal gene expression in cancer cells. Consequently, cancer phenotypes such as genetic and epigenetic instabilities, and also the presence of cells with stem cell-like properties, may result from inaccurate and aberrant patterns of gene expression generated by microenvironmental alterations. Finally, the therapeutic implications of this view are discussed.