tetracycline and Demyelinating-Diseases

To identify infectious diseases likely involved in MS, the author previously correlated the geographical distribution of MS with the global distribution of tick-borne diseases. Tick-borne infectious agents include mollicutes or mycoplasmas. The current paper reviews evidence that mollicutes, especially spiroplasmas, or their viruses could be the initial exposure that causes MS. Mollicute infections, including the effects of their toxins, can be treated or prevented with gold salts or tetracyclines. If further research recommended by this review finds a role of mycoplasmas in MS, treatment of MS with gold with tetracycline should be evaluated.

Topics: Animals; Demyelinating Diseases; Gold; Humans; Multiple Sclerosis; Plasmids; Tenericutes; Tetracycline; Tick-Borne Diseases; Ticks

The quaking viable mice have myelination defects and develop a characteristic tremor 10 d after birth. The quaking gene encodes at least five alternatively spliced QUAKING (QKI) isoforms that differ in their C-terminal 8--30-amino-acid sequence. The reason for the existence of the different QKI isoforms and their function are unknown. Here we show that only one QKI isoform, QKI-7, can induce apoptosis in fibroblasts and primary rat oligodendrocytes. Heterodimerization of the QKI isoforms results in the nuclear translocation of QKI-7 and the suppression of apoptosis. The unique C-terminal 14 amino acids of QKI-7 confers the ability to induce apoptosis to heterologous proteins such as the green fluorescent protein and a QKI-related protein, Caenorhabditis elegans GLD-1. Thus, the unique C-terminal sequences of QKI-7 may function as a life-or-death 'sensor' that monitors the balance between the alternatively spliced QKI isoforms. Moreover, our findings suggest that nuclear translocation is a novel mechanism of inactivating apoptotic inducers.

Topics: 3T3 Cells; Adenoviridae; Alternative Splicing; Amino Acid Sequence; Animals; Apoptosis; Cell Nucleus; Cells, Cultured; Demyelinating Diseases; Dimerization; Genetic Vectors; HeLa Cells; Humans; Mice; Mice, Quaking; Molecular Sequence Data; Oligodendroglia; Protein Isoforms; Protein Multimerization; Protein Sorting Signals; Protein Transport; Rats; Recombinant Fusion Proteins; RNA-Binding Proteins; Sequence Alignment; Structure-Activity Relationship; Tetracycline; Transcriptional Activation; Transfection

Charcot-Marie-Tooth disease type 1A, a hereditary demyelinating neuropathy, is usually caused by overexpression of peripheral myelin protein 22 (PMP22) due to a genomic duplication. We have generated a transgenic mouse model in which mouse pmp22 overexpression can be regulated. In this mouse model, overexpression of pmp22 occurs specifically in Schwann cells of the peripheral nerve and is switched off when the mice are fed tetracycline. Overexpression of pmp22 throughout life (in the absence of tetracycline) causes demyelination. In contrast, myelination is nearly normal when pmp22 overexpression is switched off throughout life by feeding the mice tetracycline. When overexpression of pmp22 is switched off in adult mice, correction begins within 1 week and myelination is well advanced by 3 months (although the myelin sheaths are still thinner than normal), indicating that the Schwann cells are poised to start myelination. Upregulation of the gene in adult mice (which had previously had normal pmp22 expression) is followed by active demyelination within 1 week, which had plateaued by 8 weeks. This indicates that Schwann cells with mature myelin are sensitive to increased amounts of pmp22 such that they rapidly demyelinate. Thus, demyelination can largely be corrected within a few months, but the correction will be sensitive to subsequent upregulation of pmp22.

Topics: Animals; Charcot-Marie-Tooth Disease; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Myelin Proteins; Myelin Sheath; Neural Conduction; Phenotype; Regulatory Sequences, Nucleic Acid; RNA, Messenger; Schwann Cells; Tetracycline; Tetracycline Resistance