Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington's disease.
OBJECTIVE
Recent data suggest that wild type huntingtin can protect against apoptosis in the testis of mice expressing full length huntingtin transgenes with expanded CAG repeats. It is not clear if this protective effect was confined to particular cell types, or if wild type huntingtin exerted its protective effect in this model by simply reducing the formation of toxic proteolytic fragments from mutant huntingtin.


METHODS
We cotransfected neuronal (SK-N-SH, human neuroblastoma) and non-neuronal (COS-7, monkey kidney) cell lines with HD exon 1 (containing either 21 or 72 CAG repeats) construct DNA and either full length wild type huntingtin or pFLAG (control vector).


RESULTS
Full length wild type huntingtin significantly reduced cell death resulting from the mutant HD exon 1 fragments containing 72 CAG repeats in both cell lines. Wild type huntingtin did not significantly modulate cell death caused by transfection of HD exon 1 fragments containing 21 CAG repeats in either cell line.


CONCLUSIONS
Our results suggest that wild type huntingtin can significantly reduce the cellular toxicity of mutant HD exon 1 fragments in both neuronal and non-neuronal cell lines. This suggests that wild type huntingtin can be protective in different cell types and that it can act against the toxicity caused by a mutant huntingtin fragment as well as against a full length transgene.
Ho
L W
LW
Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms of Disease, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
Brown
R
R
Maxwell
M
M
Wyttenbach
A
A
Rubinsztein
D C
DC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D005091:Exons / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D019076:Transgenes / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D014407:Tumor Cells, Cultured
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010446:Peptide Fragments