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Human Molecular Genetics Advance Access published online on October 18, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm301
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

HYPK, a huntingtin interacting protein, reduces aggregates and apoptosis induced by N-terminal huntingtin with 40 glutamines in Neuro2A cells and exhibits chaperone like activity

Swasti Raychaudhuri1,2, Mithun Sinha1, Debashis Mukhopadhyay1 and Nitai P. Bhattacharyya1,2,*

1 Structural Genomics Section, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700 064, India 2 Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700 064, India

* Corresponding Author: Nitai P. Bhattacharyya, Ph.D, Professor, Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700 064, India. Tel: 9133-2337-5345-49; Fax: 0091-33-2337-4637; E-Mail: nitai_sinp{at}yahoo.com

Received June 1, 2007; Revised October 10, 2007; Accepted October 10, 2007

Expansion of polymorphic glutamine (Q) numbers present at the protein Huntingtin (Htt) beyond 36Q results in its misfolding and aggregation and the aggregates recruit several other proteins. Here we show that HYPK, initially identified as an Htt-interacting partner by yeast two hybrid assay, physically interacts with N-terminal Htt in Neuro2A cells and alters the numbers and distribution of aggregates formed by N-terminal Htt with 40Q. HYPK also alters the kinetics of mutated N-terminal Htt mediated aggregate formation. FRAP studies reveal that over-expression of HYPK results in the appearance of Htt-poly Q aggregates, which upon bleaching recovers ~ 80% of initial fluorescence intensity within 6 minutes. FLIP studies indicate loss off fluorescence intensity of the aggregates with time in presence of HYPK. Over-expression of this protein reduces poly Q mediated caspase 2, caspase 3 and caspase 8 activations whereas {gamma} ray induced activations of these enzymes are not affected. In vitro and in vivo studies demonstrate that HYPK possesses a novel chaperone-like activity. We conclude that, HYPK, without having any sequence similarity with known chaperones, plays an effective role in protecting neuronal cells against apoptosis induced by mutated N-terminal Htt by modulating the aggregate formation.


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