. A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell. 2005 Jan 14;120(1):73-84. PubMed.

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  1. Time for the ubiquitin-proteasome system
    Most likely, dysfunction of the ubiquitin-proteasome system (UPS) contributes to the neuropathogenesis of various types of conformational diseases (for example, Alzheimer, Parkinson, and Huntington diseases). The past decade has revealed a surprising complexity of this system, especially with regard to enzymes such as E2 conjugating enzymes (for example E2-25K-Hip2) and the numerous E3 ligating proteins (for example CHIP, parkin). For a good review, see Pickart and Cohen, 2004). In addition, other proteolytic factors were identified, for example, CDC48/p97. These were coined “E4 enzymes.” They escort ubiquitinated proteins to the proteasome, where they are then degraded. This paper places these various E4 factors in a sequential order in yeast studies, as illustrated in their figure 7 on page 81 (see also commentary by Huibregtse, 2005).

    It is now time to verify the relevance of these E4 factors for neuropathogenesis in neuronal cells and in postmortem tissue. Alzheimer disease clearly intersects with the UPS. This trend is evident in the literature (see Song and Jung, 2004; Cookson, 2004) and was also on display at the most recent Alzheimer meeting in Philadelphia and that of the Society for Neuroscience conference in San Diego. It is to be expected that the next decade will see the dissection of the UPS and its relevance in neurodegeneration.

    Of course, one needs to realize that the UPS is only one way to degrade proteins. Moreover, when the capacity of the UPS is exceeded, autophagy (i.e., the lysosomal/vacuole system), which is essential for the elimination of aggregates, is induced (see, for example, Klionsky, 2005; Nixon, 2005).

    References:

    . Proteasomes and their kin: proteases in the machine age. Nat Rev Mol Cell Biol. 2004 Mar;5(3):177-87. PubMed.

    . UPS shipping and handling. Cell. 2005 Jan 14;120(1):2-4. PubMed.

    . Alzheimer's disease meets the ubiquitin-proteasome system. Trends Mol Med. 2004 Nov;10(11):565-70. PubMed.

    . Roles of the proteasome in neurodegenerative disease: refining the hypothesis. Ann Neurol. 2004 Sep;56(3):315-6. PubMed.

    . The molecular machinery of autophagy: unanswered questions. J Cell Sci. 2005 Jan 1;118(Pt 1):7-18. PubMed.

    . Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol Aging. 2005 Mar;26(3):373-82. PubMed.