The reviewed article is ‘The Ubiquitin-Proteasome Pathway in Huntington’s Disease’ by Siddhartha Mitra and Steven Finkbeiner and freely available here. The authors argue for a role of the Ubiquitin-Proteasome Pathway in the pathogenesis of Huntington’s Disease. The authors first of all argue that the Huntingtin Mutant Protein confers a gain of function by citing evidence that demonstrates that loss of function of the Huntingtin Protein leads to a different type of pathology. Having established a gain of function for the Huntingtin protein and assuming (not unreasonably) that it directly mediates the HD pathology, the authors then cite evidence showing that the protein’s actions can be reversed in models of Huntington’s Disease. The cited studies provide evidence that the ubiquitin-proteasome pathway is needed to reverse the mutant protein induced pathology. Here then is the link between Ubiquitin and Huntingtin which forms an essential part of the subsequent arguments. The occurrence of both mutant Huntingtin and Ubiquitin in inclusion bodies, the possible protective role of these inclusion bodies and the possibility that the mutant Huntingtin protein may be impairing the function of Ubiquitin are all discussed.
The authors however are limited in the remainder of the discussion by the relatively large number of uncertainties in the pathways that might be involved although they use detective work to suggest promising avenues for future research. If the ubiquitin-proteasome pathways are involved in the breakdown of the mutant Huntingtin protein then the next question is which mediators are involved. This is where things get tricky:-
‘The challenges of identifying the ligase that ubiquinates a particular protein substrate is akin to that of identifying a kinase responsible for phosphorylating a particular target – functional compensation muddles the interpretation of genetic approaches‘
Nevertheless they identify some candidate ligands for the role of ubiquinators of the mutant Huntingtin protein before finishing with a discussion of possible therapeutic strategies. As there is evidence of the involvement of Ubiquitin in several other neurodegenerative conditions perhaps we are seeing the beginning of an elucidation of a very important pathological process, the understanding of which may yield significant clinical benefit. Only time and further research will tell.
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