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SAGE KE Bulletin Board

Highlights of the 34th Annual Meeting of the Society for Neuroscience 2004 in San Diego:

4 November 2004

Dietmar R. Thal

Valosin-containing protein (VCP): Role in neurodegeneration

VCP, a member of the AAA-ATPase superfamily, has been associated with a wide variety of essential cellular protein pathways comprising nuclear envelope reconstruction, cell cycle, postmitotic Golgi reassembly, suppression of apoptosis and DNA damage response.(Kondo et al., 1997; Rabouille et al., 1998; Meyer et al., 2000; Hetzer et al., 2001; Rabinovich et al., 2002) In addition to binding to expanded polyglutamine protein aggregates,(Hirabayashi et al., 2001) VCP has been postulated to play a pivotal role in ubiquitin-dependent protein degradation.(Dai und Li, 2001) Schroeder et al. (Schroeder et al., 2004) presented a report of a patient with a valosin-containing protein mutation leading to an inclusion body myopathy with frontotemporal dementia. In addition to the well known cytoplasmic ubiquitin and VCP-containing inclusion they showed nuclear inclusion bodies containing both of the before mentioned proteins as well. In so doing, this study points in addition to the expanded polyglutamine protein aggregate binding capacity to a pathogenetic role of VCP for nuclear inclusion body disorders. Moreover, Klein et al. (Klein et al., 2004) showed that VCP is phosphorylated by the anti-apoptotic protein Akt and links Akt to the protein degradation pathway in the ER. Another interaction partner of VCP in endoplasmatic protein degradation is Dorfin (Ishigaki et al., 2004). Dorfin in RING-IBR type ubiquitin ligase which ubiquitilates the superoxide dismutase (SOD1) in amyotrophic lateral sclerosis. VCP thereby interacts with Dorfin. This interaction is required for the ubiquitin ligase function of Dorfin. Taken together, 1) VCP has a key function in protein ubiquitilation in the endoplasmic protein degradation pathway, thereby, being regulated through phosphorylation by Akt and through interaction with Dorfin. These multiple interactions in protein degradation pathways points to an important role of VCP in protein degradation disorders such as amyotrophic lateral sclerosis and inclusion body myopathies. 2) VCP mutations can be responsible for a nuclear inclusion body type of frontotemporal dementia. Thus, it is tempting to speculate that VCP plays a pathogenetic role in nuclear inclusion body diseases as well. A further argument favoring this hypothesis is: VCP has a polyglutamine protein binding capacity involved in Huntington’s disease and spinocerebellar ataxia type III (SCA III) (Hirabayashi et al., 2001; Higashiyama et al., 2002).

Dai RM und Li CC (2001) Valosin-containing protein is a multi- ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol 3:740-744. Hetzer M, Meyer HH, Walther TC, Bilbao-Cortes D, Warren G und Mattaj IW (2001) Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly. Nat Cell Biol 3:1086-1091. Higashiyama H, Hirose F, Yamaguchi M, Inoue YH, Fujikake N, Matsukage A und Kakizuka A (2002) Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration. Cell Death Differ 9:264-273. Hirabayashi M, Inoue K, Tanaka K, Nakadate K, Ohsawa Y, Kamei Y, Popiel AH, Sinohara A, Iwamatsu A, Kimura Y, Uchiyama Y, Hori S und Kakizuka A (2001) VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration. Cell Death Differ 8:977-984. Ishigaki S, Hishikawa N, Niwa J, Kakizuka A, Tanaka K und Sobue G (2004) Physical and functional interaction between Dorfin and VCP that are colocalized in ubiquitilated inclusions in neurodegenerative disorders. 2004 Abstract Viewer/Inenerary Planner:Program No. 340.318. Klein J, Barati M, Gozal E, Gozal D, Scherzer J, Trent J, Wu R und Rane M (2004) Association of valosin-containing protein p97 and Akt during hypoxia in the rat hippocampus. 2004 Abstract Viewer/Inenerary Planner:Program No. 663.667. Kondo H, Rabouille C, Newman R, Levine TP, Pappin D, Freemont P und Warren G (1997) p47 is a cofactor for p97-mediated membrane fusion. Nature 388:75 -78. Meyer HH, Shorter JG, Seemann J, Pappin D und Warren G (2000) A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. Embo J 19:2181-2192. Rabinovich E, Kerem A, Frohlich KU, Diamant N und Bar-Nun S (2002) AAA- ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 22:626-634. Rabouille C, Kondo H, Newman R, Hui N, Freemont P und Warren G (1998) Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro. Cell 92:603-610. Schroeder R, Watts GD, Pauls K, Mehta SG, Hans V, Evert BO, Kimonis VE und Thal DR (2004) Mutations in valosin-containing protein gene causes fronto- temporo-striatal dementia with nuclear inclusions and inclusion body myopathy. 2004 Abstract Viewer/Inenerary Planner:Program No. 97.12.

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