Abstract
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.
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Abbreviations
- CBS:
-
cystathionine beta-synthase
- FIP2:
-
Rab11 family-interacting protein 2
- GRB2:
-
growth factor receptor-bound protein 2
- HD:
-
Huntington's disease
- HIP1:
-
huntingtin interacting protein 1
- HIP14:
-
huntingtin interacting protein 14
- N-CoR:
-
nuclear receptor corepressor 1
- NMDA:
-
N-methyl-D-aspartic acid
- PACSIN1:
-
protein kinase C and casein kinase substrate in neurons protein 1
- poly-Q:
-
polyglutamine
- PSD95:
-
postsynaptic density protein 95
- QA:
-
quinolinic acid
- RasGAP:
-
RAS-GTPase-activating protein
- SH3:
-
Src-homology 3
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Acknowledgements
We thank Ruben Smith and Mark Denham as well as the anonymous reviewers for helpful comments on the manuscript and Denis Soulet for support with artwork. TZ is supported by The Nordic Centre of Excellence Programme in Molecular Medicine 2004–2009 entitled ‘Neurodegeneration’.
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Zuchner, T., Brundin, P. Mutant huntingtin can paradoxically protect neurons from death. Cell Death Differ 15, 435–442 (2008). https://doi.org/10.1038/sj.cdd.4402261
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DOI: https://doi.org/10.1038/sj.cdd.4402261
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