Song S, Kim SY, Hong YM, Jo DG, Lee JY, Shim SM, Chung CW, Seo SJ, Yoo YJ, Koh JY, Lee MC, Yates AJ, Ichijo H, Jung YK.
Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity.
Mol Cell. 2003 Sep;12(3):553-63.
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A Link between Aβ and the Ubiquitin-Proteasome System
The paper by Song et al. is a surprising study on the connection between amyloid-β and proteasome inhibition through E2-25K/Hip2 (a ubiquitin-conjugating enzyme) and frameshift ubiquitin (Van Leeuwen et al., 1998). Of course, this study raises a number of questions. For instance, how does Aβ1-42 induce E2-25K/Hip2 activation and how specific is the effect when scrambled controls are used? Furthermore, it will be of interest to study the influence of E2-25K/Hip2 on ubiquitination of Lys29 in UBB+1protein (Lindsten et al., 2002). In my opinion, the translation of the results towards neuropathology in Alzheimer’s disease could have been better. Data from controls (“normal”), whose age is not mentioned, would be much more informative if young and aged (without and with neuropathology, respectively) nondemented controls had been included. Furthermore, the resolution of these photographs is such that the localization of anti-E2-25K/Hip2 is unclear: It may be present in dystrophic neurites. If it is co-localized with Aβ in the plaque, one might wonder what is the interpretation of its co-localization with UBB+1 in cerebral cortical cells (of which area?). The latter is important, as Aβ and UBB+1 protein are present in different cellular compartments. Moreover, it is unclear why the neurofibrillary tangle, a major hallmark for Alzheimer’s disease, is not discussed in the paper.
Nevertheless, this is an original contribution which will help to understand conformational diseases such as Alzheimer’s. Congratulations are, therefore, in order for the authors and further contributions from this group are awaited eagerly.
Van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, Grosveld FG, Peter J, Burbach H, Hol EM.
Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients.
Science. 1998 Jan 9;279(5348):242-7.
Lindsten K, de Vrij FM, Verhoef LG, Fischer DF, Van Leeuwen FW, Hol EM, Masucci MG, Dantuma NP.
Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation.
J Cell Biol. 2002 Apr 29;157(3):417-27.