Mutant valosin‐containing protein causes a novel type of frontotemporal dementia

Schröder, Rolf; Watts, Gdj; Mehta, SG; Evert, BO; Broich, P; Fließbach, Klaus; Pauls, K. Peter; Hans, VH; Kimonis,; Thal, Dietmar Rudolf

doi:10.1002/ana.20407

Cited by 167 publications

(132 citation statements)

References 19 publications

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“…Afterwards, VCP, the highly conserved human orthologue of Cdc48p, has been identified as an apoptosis regulator in mammalian cells, making Cdc48p/VCP the first death mediator originally discovered in yeast [16,110]. VCP was shown to be a pathological effector for polyglutamineinduced neurodegeneration [110] and mutations in VCP have been connected to inclusion body formation associated with Paget disease, a dominant human disorder [111,112]. However, the mechanisms underlying VCP-mediated cell death in these human disorders remain elusive.…”

Section: Mitochondria Controlled Yeast Apoptosis Elucidates Neurodegementioning

confidence: 99%

The mitochondrial pathway in yeast apoptosis

et al. 2007

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Mitochondria are not only important for the energetic status of the cell, but are also the fatal organelles deciding about cellular life and death. Complex mitochondrial features decisive for cell death execution in mammals are present and functional in yeast: AIF and cytochrome c release to the cytosol, mitochondrial fragmentation as well as mitochondrial hyperpolarisation followed by an oxidative burst, and breakdown of mitochondrial membrane potential. The easy accessibility of mitochondrial manipulations such as repression of respiration by growing yeast on glucose or deletion of mitochondrial DNA (rho 0 ) on the one hand and the unique ability of yeast cells to grow on nonfermentable carbon sources by switching on mitochondrial respiration on the other hand have made yeast an excellent tool to delineate the necessity for mitochondria in cell death execution. Yeast research indicates that the connection between mitochondria and apoptosis is intricate, as abrogation of mitochondrial function can be either deleterious or beneficial for the cell depending on the specific context of the death scenario. Surprisingly, mitochondrion dependent yeast apoptosis currently helps to understand the aetiology (or the complex biology) of lethal cytoskeletal alterations, ageing and neurodegeneration. For example, mutation of mitochondrial superoxide dismutase or CDC48/VCP mutations, both T. Eisenberg · S. Büttner · F. Madeo ( ) Institute of Molecular Biosciences, Universitaetsplatz 2, University of Graz, 8010 Graz, Austria e-mail: frank.madeo@uni-graz.at G. Kroemer Apoptosis, Cancer, and Immunity Unit, Institut Gustave Roussy, Faculté Paris Sud-Université, Institut National de la Santé et de la Recherche Médicale, Paris XI, France implicated in several neurodegenerative disorders, are associated with mitochondrial impairment and apoptosis in yeast.

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Section: Mitochondria Controlled Yeast Apoptosis Elucidates Neurodegementioning

confidence: 99%

The mitochondrial pathway in yeast apoptosis

et al. 2007

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“…Mutant VCP is an inductor of IBMPFD, a dominant human disorder (5,6). Wild-type VCP has been described as a pathological mediator for human polyglutamine diseases (7,10,51).…”

Section: Mitochondria Are Crucially Impaired In Apoptotic Cdc48mentioning

confidence: 99%

“…Mutations in VCP have been associated with "inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia" (IBMPFD), a dominant human disorder (5,6). A genetic screening of a Drosophila model for human polyglutamine diseases, a class of inherited neurodegenerative disorders, identified the Drosophila homologue of Cdc48p/VCP as a modulator of apoptotic cell death (7), leading these authors to propose VCP as a pathological effector for polyglutamine-induced neurodegeneration.…”

mentioning

confidence: 99%

Crucial Mitochondrial Impairment upon CDC48 Mutation in Apoptotic Yeast

Braun¹,

Zischka

Madeo

et al. 2006

Journal of Biological Chemistry

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Mutation in CDC48 (cdc48 S565G ), a gene essential in the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway, led to the discovery of apoptosis as a mechanism of cell death in the unicellular organism Saccharomyces cerevisiae. Elucidating Cdc48p-mediated apoptosis in yeast is of particular interest, because Cdc48p is the highly conserved yeast orthologue of human valosin-containing protein (VCP), a pathological effector for polyglutamine disorders and myopathies. Here we show distinct proteomic alterations in mitochondria in the cdc48 S565G yeast strain. These observed molecular alterations can be related to functional impairment of these organelles as suggested by respiratory deficiency of cdc48 S565G cells. Mitochondrial dysfunction in the cdc48 S565G strain is accompanied by structural damage of mitochondria indicated by the accumulation of cytochrome c in the cytosol and mitochondrial enlargement. We demonstrate accumulation of reactive oxygen species produced predominantly by the cytochrome bc 1 complex of the mitochondrial respiratory chain as suggested by the use of inhibitors of this complex. Concomitantly, emergence of caspase-like enzymatic activity occurs suggesting a role for caspases in the cell death process. These data strongly point for the first time to a mitochondrial involvement in Cdc48p/VCPdependent apoptosis.Fundamental cellular processes, such as the formation of organelles (ER,3 Golgi apparatus, and the nuclear envelope), or ubiquitin-dependent ER-associated protein degradation (ERAD) have been linked to the yeast protein Cdc48p and its highly conserved mammalian orthologue VCP (1-4). Mutations in VCP have been associated with "inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia" (IBMPFD), a dominant human disorder (5, 6). A genetic screening of a Drosophila model for human polyglutamine diseases, a class of inherited neurodegenerative disorders, identified the Drosophila homologue of Cdc48p/VCP as a modulator of apoptotic cell death (7), leading these authors to propose VCP as a pathological effector for polyglutamine-induced neurodegeneration. However, the cellular mechanisms underlying VCP-mediated cell death in these human disorders remain largely unknown. Apoptotic phenotypes in cells expressing mutated Cdc48p/ VCP have originally been described in budding yeast (8) and were thereafter confirmed in mammalian cell cultures (9, 10), in trypanosomes (11), and in zebrafish (12). Notably, Cdc48p was the first apoptotic mediator found in Saccharomyces cerevisiae (8). The expression of a point-mutated CDC48 gene (cdc48 S565G ) leads to a characteristic apoptotic phenotype: phosphatidylserine externalization, DNA fragmentation, chromatin condensation, nuclear fragmentation, and vacuolization (8, 13). These results obtained in the cdc48 S565G strain initiated the establishment of yeast as a model to study evolutionary conserved mechanisms of apoptotic regulation (14 -16).Mitochondria play a crucial role in many apoptotic pathways in ...

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“…The N-terminal region (N-domain) of VCP is involved in the interaction with various adaptors that direct VCP to various cellular events. The identified IBMPFD mutations are highly clustered in the N-and D1 domains of VCP (36,47,50). Interestingly, all mutation hot spots are located at the interface between the N-and D1 domains (51).…”

Section: Introductionmentioning

confidence: 97%

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

Wang¹,

Shih²,

Chen³

et al. 2011

J. Clin. Invest.

104

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Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1 +/-mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.

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Mutant valosin‐containing protein causes a novel type of frontotemporal dementia

Cited by 167 publications

References 19 publications

The mitochondrial pathway in yeast apoptosis

The mitochondrial pathway in yeast apoptosis

Crucial Mitochondrial Impairment upon CDC48 Mutation in Apoptotic Yeast

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

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