Wednesday, July 31, 2013

HDAC6, aggresome and Huntington's disease

I learned this piece of knowledge when I was reviewing the gene description for the update list of Factorbook (factorbook.org).

HDAC6 is a member of histone deacetylase/acuc/apha family. As the other member in the family, HDAC6 possesses histone deacetylase activity and represses transcription. But one other interesting function it has is to act as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.

Here is what I got from wikipedia page of aggresome:
The failure of polypeptides to adopt their proper structure is a major threat to cell function and viability. Consequently, elaborate systems have evolved to protect cells from the deleterious effects of misfolded proteins. Cells mainly deploy 3 mechanisms to counteract misfolded proteins:

1) up-regulating chaperones to assist protein refolding,
2) proteolytic degradation of the misfolded/damaged proteins involving ubiquitin–proteasome and autophagy–lysosome systems, and
3) formation of detergent-insoluble aggresomes by transporting the misfolded proteins along microtubules to a region near the nucleus.
Here is a figure illustrating the last two mechanisms:

Aggregated proteins are transported to the microtubule-organizing center (MTOC) by retrograde transport on microtubules (+ and - ends indicated) by dynein motor complexes. At the MTOC they are surrounded by a cage of intermediate filaments, such as vimentin (IF). Aggresomes have high concentrations of components of the ubiquitin–proteosome pathway of protein degradation, including HSP chaperonins, ubiquitin, and proteosomes. (Credit: http://www.nature.com/onc/journal/v24/n52/fig_tab/1209040f4.html)

While the mechanisms why these aggregates form (despite the existence of cellular machinery to recognize and degrade misfolded protein) and how they are delivered to cytoplasmic inclusions are not known, aggregation of misfolded protein in cytoplasmic inclusions is common to many age-related neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. It may be because these neurodegenerative diseases are mostly repeated expansion disease, they form aggregation with the inserted trinucleotide/peptide stretch. 

But why and how HDAC6 functions in the pathway of aggresome formation? What makes it different from other histone deacetylase?

Here is a recent paper might worthy to read:

HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?
http://www.molecularneurodegeneration.com/content/8/1/7/

3 comments:

  1. Amazing mechanisms...

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