Classical transgenic and gene-targeted mouse mutants are powerful model systems in which to study the pathogenesis of neurodegenerative diseases. However, a number of issues of fundamental importance to neurodegenerative research cannot be addressed using classical techniques. These include identification of the earliest events in disease pathogenesis anda determination of whether a particular pathogenic protein produces a inexorable or a reversible disease process. Both of these issues have profound implications for the rational development of new therapies. To address these questions, genetic techniques that allow pathogenic proteins to be expressed or knocked out with temporal and regional specificity have been developed. We have reviewed these systems, highlighting the tetracycline-regulated system because of its demonstrated utility in mice and its reversibility. These regulatable systems are a new and powerful tool for the neurobiologist and allow one to address a new set of important questions in an in vivo setting.
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