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An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with Huntington's disease (HD) together with rod-like tau deposits along neuronal nuclei. These tau nuclear rods show an ordered filamentous ultrastructure and can be found filling the neuronal nuclear indentations previously reported in HD brains. Finally, alterations in serine/arginine-rich splicing factor-6 coincide with tau missplicing, and a role of tau in HD pathogenesis is evidenced by the attenuation of motor abnormalities of mutant HTT transgenic mice in tau knockout backgrounds., Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease (AD), progressive supranuclear palsy, corticobasal degeneration, Pick's disease and FTDP-17, that are characterized by altered metabolism and deposition of the [...]

Use of lithium, the mainstay for treatment of bipolar disorder, is limited by its frequent neurological side effects and its risk for overdose-induced toxicity. Recently, lithium has also been proposed as a treatment for Alzheimer disease and other neurodegenerative conditions, but clinical trials have been hampered by its prominent side effects in the elderly. The mechanisms underlying both the positive and negative effects of lithium are not fully known. Lithium inhibits glycogen synthase kinase-3 (GSK-3) in vivo, and we recently reported neuronal apoptosis and motor deficits in dominant-negative GSK-3-transgenic mice. We hypothesized that therapeutic levels of lithium could also induce neuronal loss through GSK-3 inhibition. Here we report induction of neuronal apoptosis in various brain regions and the presence of motor deficits in mice treated chronically with lithium. We found that GSK-3 inhibition increased translocation of nuclear factor of activated T cells c3/4 (NFATc3/4) transcription factors to the nucleus, leading to increased Fas ligand (FasL) levels and Fas activation. Lithium-induced apoptosis and motor deficits were absent when NFAT nuclear translocation was prevented by cyclosporin A administration and in Fas-deficient lpr mice. The results of these studies suggest a mechanism for lithium-induced neuronal and motor toxicity. These findings may enable the development of combined therapies that diminish the toxicities of lithium and possibly other GSK-3 inhibitors and extend their potential to the treatment of Alzheimer disease and other neurodegenerative conditions., Introduction Since its introduction into psychiatric pharmacotherapy 60 years ago, lithium remains the most effective agent in the treatment and prophylaxis of major mood disorders, particularly bipolar disorder (BD) (1-4). [...]

I. Introduction II. The Tau Gene A. Human tau gene polymorphism B. Human tau gene expression III. Saithoin IV. Tau Protein A. Regions, domains, and motifs V. Cellular and Subcellular [...]

A common histopathological hallmark of most neurodegenerative diseases is the presence of aberrant proteinaceous inclusions inside affected neurons. Because these protein aggregates are detected using antibodies against components of the ubiquitin--proteasome system (UPS), impairment of this machinery for regulated proteolysis has been suggested to be at the root of neurodegeneration. This hypothesis has been difficult to prove in vivo owing to the lack of appropriate tools. The recent report of transgenic mice with ubiquitous expression of a UPS-reporter protein should finally make it possible to test in vivo the role of the UPS in neurodegeneration.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/S0092-8674(00)80623-6 Byline: Ai Yamamoto (1), Jose J Lucas (1), Rene Hen (1) Abstract: Neurodegenerative disorders like Huntington's disease (HD) are characterized by progressive and putative irreversible clinical and neuropathological symptoms, including neuronal protein aggregates. Conditional transgenic models of neurodegenerative diseases therefore could be a powerful means to explore the relationship between mutant protein expression and progression of the disease. We have created a conditional model of HD by using the tet-regulatable system. Mice expressing a mutated huntingtin fragment demonstrate neuronal inclusions, characteristic neuropathology, and progressive motor dysfunction. Blockade of expression in symptomatic mice leads to a disappearance of inclusions and an amelioration of the behavioral phenotype. We thus demonstrate that a continuous influx of the mutant protein is required to maintain inclusions and symptoms, raising the possibility that HD may be reversible. Author Affiliation: (1) Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA Article History: Received 29 November 1999; Revised 3 March 2000

In recent years, cloning has revealed the existence of no less than 14 mammalian 5-HT receptors, as well as evidence that isoforms of the 5-H[T.sub.4] and 5-H[T.sub.7] receptors are generated by alternative splicing. In addition, molecular biology techniques have provided new tools with which to study the function of 5-HT receptors. For example, new technologies are emerging that will allow the generation of either inducible or tissue-specific knockouts (or both). In this review Jose Lucas and Rene Hen focus on the characteristics of the most recently cloned receptors and the contribution of molecular biology to the understanding of 5-HT receptor function.