What can animal models teach us on the pathogenesis of neurodegenerative diseases?

Author: O. Riess
Submitted: Sunday 12th of September 2010 09:01:50 AM
Submitted by: egf
Educational levels: expert, qc3


Numerous neurodegenerative diseases are characterized by protein aggregates in specific brain regions, although they are accumulating in different cellular compartments. One group of diseases which are caused by polyglutamine expansions in the respective gene such as Huntington’s disease and spinocerebellar ataxias, manifest with intranuclear protein aggregates. During my talk I will describe how transgenic mouse models of autosomal dominantly inherited Spinocerebellar Ataxia Type 3 (SCA3) will help us to understand pathogenic pathways, and concluding from this information, what strategies we may have to choose to define treatment targets. SCA3 is caused by an expansion of a CAG trinucleotid repeat in the MJD1 gene. The resulting expression of an elongated polyglutamine repeat in the ataxin-3 protein leads to the formation of intraneuronal inclusions and degeneration of affected brain regions. Natural existing animal models harbouring this mutation have not been described yet. In order to further investigate the pathology of the disease and to have models mimicking the human condition, we and others generated transgenic mouse models of SCA3/MJD with different CAG repeat length. Based on the characterization of these models one can conclude that (1) transgenic mouse models reflecting the human disease have been successfully generated, (2) these models present with progressive neurological und neuropathological features including intranuclear inclusions and cell death, (3) the age at onset and the disease progression depends on the expanded CAG repeat length and the level of transgene expression, and (4) the differences between the different mouse lines generated depend also on the different promoters used to drive transgene expression. One can also conclude that transgenic mice overexpressing CAG repeats in the normal human repeat range do not develop any phenotype. Finally, generating mouse models with a nuclear localization signal (NLS) and other models with a nuclear export signal (NES) attached to full length ataxin-3 clearly indicated the nucleus as the subcellular site of pathology indicating that prevention of its nuclear localization might be a promising target of potential treatment strategies. That therapeutic intervention is clearly an option even in already affected patients, has been demonstrated by our recent inducible mouse model in which turning off transgene expression in neurologically and neuropathologically affected mice led to reversibility of the phenotype.


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O. Riess. What can animal models teach us on the pathogenesis of neurodegenerative diseases?. EUROGENE portal. September 2010. online: http://eurogene.open.ac.uk/content/what-can-animal-models-teach-us-pathogenesis-neurodegenerative-diseases



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