Halawani D, Tessier S, Anzellotti D, Bennett DA, Latterich M, Leblanc AC. Identification of Caspase-6-mediated processing of the valosin containing protein (p97) in Alzheimer's disease: a novel link to dysfunction in ubiquitin proteasome system-mediated protein degradation. J Neurosci. 2010 Apr 28;30(17):6132-42. PubMed.
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University Maastricht
Time for the Ubiquitin-Proteasome System #3
These papers look very interesting and show the relevance in Alzheimer disease of an efficient working protein quality control by the ubiquitin-proteasome system (UPS) and by autophagy, two systems that show crosstalk. I am organizing a satellite on this subject soon at a FENS meeting.
The papers agree with the idea that an efficient working UPS is very relevant for preventing and/or delaying AD; see our recent mini-review in Neurodegenerative Diseases (Dennissen et al., 2010). These two papers add again pieces of the puzzle to aid in dissecting AD pathogenesis, particularly the Halawani paper in MCI (see also my two previous comments Time for the ubiquitin-proteasome system and Time for the Ubiquitin-Proteasome System #2: Dendritic Spines).
The paper by Halawani reports on the ubiquitin-escort protein valosin (p97) as a new substrate for caspase 6 in AD, and as a novel mechanism of UPS impairment in AD. Caspase-6 expression is activated in AD and other substrates of caspase-6 are cytoskeletal proteins, which are critical for axonal function. In this regard, there is a link with a paper showing that misframed ubiquitin (UBB+1) causes neuritic beading (see Tan et al., 2007). P97 facilitates UPS-mediated degradation in several pathways, including the ubiquitin fusion degradation pathway (UFD). Moreover, UBB+1 is the first-reported naturally occurring UFD substrate (see Lindsten et al., 2002). The present data open an avenue for further research, e.g., colocalization of Caspase-6 cleaved P97, UBB+1 and caspase-6 in AD.
The paper of Kurup et al. provides biochemical evidence that the enzyme “striatal-enriched protein tyrosine phosphatase 61(STEP 61)” is post-translationally modified by ubiquitin after Aβ-mediated NMDA receptor endocytosis in a mouse model of AD of Karen Hsiao (Tg2576) and supported by studies in postmortem tissue of AD prefrontal cortex. This group indicates that decreased STEP 61 turnover is an important consequence of a dysfunctional UPS, and links directly to an impairment of normal NMDAR trafficking at synapses. Thus, here again a link between Aβ and ubiquitin is provided, and the present report is in agreement with previous studies (see Song et al., 2003). Since a unique model for neuronal proteasomal inhibition and a behavioral phenotype became recently available via Jackson Laboratories (see also Fischer et al., 2009), relevant experiments are now possible.
References:
Tan Z, Sun X, Hou FS, Oh HW, Hilgenberg LG, Hol EM, Van Leeuwen FW, Smith MA, O'Dowd DK, Schreiber SS. Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration. Cell Death Differ. 2007 Oct;14(10):1721-32. PubMed.
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. PubMed.
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. PubMed.
Fischer DF, van Dijk R, van Tijn P, Hobo B, Verhage MC, van der Schors RC, Li KW, van Minnen J, Hol EM, Van Leeuwen FW. Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol Aging. 2009 Jun;30(6):847-63. PubMed.
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