Genetic modeling of neurodegenerative diseases in mice
Neurodegenerative diseases are characterized by profound loss of certain neuronal populations and are associated with mitochondrial and proteasomal dysfunction, alteration of cellular defense mechanisms and oxidative stress. However, the exact molecular mechanisms of neurodegeneration remain to be unraveled and current pharmacotherapy provides only symptomatic cure. Although genetic mutations responsible for familial cases are known (e.g. in Alzheimer’s and Parkinson’s disease), genetic animal models often do not cover all the cardinal pathological features. This is also true for transgenic models of Huntington’s disease – one of the few neurodegenerative diseases with a known genetic cause. We applied a novel approach to generate mouse models of neurodegenerative diseases based on the activation of an endogenous suicide mechanism achieved by genetic ablation of the transcription initiation factor IA (TIF-IA). Loss of TIF-IA blocks the synthesis of ribosomal RNA leading to nucleolar disruption and p53-mediated apoptosis. We used conditional inactivation of the gene encoding TIF-IA by the Cre/loxP system to induce selective loss of different neuronal populations in mice. Deletion of TIF-IA leads to rapid loss of neuronal progenitors and progressive loss of postmitotic neurons. In dopaminergic neurons and striatal dopaminoceptive neurons nucleolar disruption results in mutants showing respectively the typical phenotype of either Parkinson’s disease (preferential degeneration of dopaminergic neurons in substantia nigra, depletion of dopamine in the striatum and typical motor dysfunctions) or Huntington’s disease (loss of medium spiny neurons in striatum, impairment of motion control and clasping behavior). In addition, cellular changes associated with nucleolar disruption recapitulate some events associated with neurodegeneration in response to oxidative stress. These mutant mice may contribute to the identification and validation of new therapeutic targets.
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