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

Halawani, Dalia; Tessier, Sylvain; Anzellotti, Dominique; Bennett, David A.; Latterich, Martin; LeBlanc, Andréa C.

doi:10.1523/jneurosci.5874-09.2010

Cited by 50 publications

(43 citation statements)

References 54 publications

(83 reference statements)

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“…These findings are paralleled by results that show the aberrant cleavage of caspase-6 substrates in brain tissue from patients suffering from HD or AD [90][91][92] . Interestingly, the disease-causing proteins mHtt, Tau and APP are substrates for caspase-6, and the abrogation of mHtt or APP cleavage in mouse models is protective and leads to a dramatic improvement of the disease phenotype 93,94 .…”

Section: Preventing Caspase-6 Cleavage Is Beneficial In Ad and Hdmentioning

confidence: 57%

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Section: Supplementary Materialsmentioning

confidence: 99%

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Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

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Section: Preventing Caspase-6 Cleavage Is Beneficial In Ad and Hdmentioning

confidence: 57%

Section: Supplementary Materialsmentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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“…19,20 Third, Casp6 cleaves valosin-containing protein resulting in the accumulation of cytosolic ubiquitinated misfolded proteins through an impairment of the ubiquitin-proteasomal system. 21 Therefore, Casp6 activation in neurons affects several neuronal structures and pathways that are essential to neuronal function.…”

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confidence: 99%

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

et al. 2014

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Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops agedependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. Cell Death and Differentiation (2014) 21, 696-706; doi:10.1038/cdd.2013; published online 10 January 2014The underlying molecular pathway for neuronal degeneration and dysfunction in Alzheimer's disease (AD) remains unknown. Yet, the identification of critical events initiating neuronal degeneration could provide a novel therapeutic approach to stem the progressive dementia of AD. We propose that Caspase-6 (Casp6), a cysteinyl protease of the caspase family, has a critical role in AD neuronal degeneration and cognitive impairment. Casp6 activity is intimately associated with the neuritic plaques (NP), neurofibrillary tangles (NFT), and neuropil threads (NPT) of AD. 1 Casp6 activity is abundant in familial AD 2 and at all stages of sporadic AD. 3 Although no Casp6 activity is present in younger brains, 1 several aged non-cognitively impaired (NCI) brains show significant amounts of Casp6 activity in the entorhinal cortex (ERC), 3 the first area showing NFT pathology in AD according to Braak staging. 4,5 Furthermore, higher levels of Casp6 activity in the ERC and cornu ammonis 1 (CA1) region of NCI brains correlate with lower episodic memory (EP) performance, one of the types of memory also affected early in AD. 6 Active Casp6 induces several parallel degenerative pathways associated with AD neuropathology. First, Casp6 activity disrupts the neuronal cytoskeleton. Casp6 cleaves neuronal microtubule protein alpha-tubulin, microtubuleassociated protein Tau, and actin-regulating post-synaptic density proteins, Spinophilin, Drebrin, and Actinins. 7 In mouse, caspase activity precedes and leads to the formation of NFT-like aggregation. 8 Casp6 activity is involved in axonal degeneration of mouse PNS neurons via amyloid precursor protein (APP) interaction with death receptor 6 9 and in nerve growth factor (NGF)-deprived dorsal root ganglion neurons. 10 Furthermore, Casp6-dependent axonal degeneration i...

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“…Protein p97 is involved in various important cellular activities including endoplasmic reticulum-associated degradation (ERAD), homotypic membrane fusion, programmed cell death, activation of B and T cells, the stress response, cell-cycle control and regulation of certain transcription factors (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The diverse biological functions of p97 implicate it in a number of neurodegenerative diseases including Alzheimer's (15), Parkinson disease, and cancer (16).…”

mentioning

confidence: 99%

Interprotomer motion-transmission mechanism for the hexameric AAA ATPase p97

Huang²,

Zhao³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Multimeric AAA ATPases represent a structurally homologous yet functionally diverse family of proteins. The essential and highly abundant hexameric AAA ATPase p97 is perhaps the best studied AAA protein, playing an essential role in various important cellular activities. During ATP-hydrolysis process, p97 undergoes dramatic conformational changes, and these changes are initiated in the C-terminal ATPase domain and transmitted across the entire length of the molecule to the N-terminal effector domain. However, the detailed mechanism of the motion transmission remains unclear. Here, we report an interprotomer motion-transmission mechanism to explain this process: The nucleotide-dependent motion transmission between the two ATPase domains of one protomer is mediated by its neighboring protomer. This finding reveals a strict requirement for interprotomer coordination of p97 during the motion-transmission process and may shed light on studies of other AAA ATPases.D1-D2 linker | tandem ATPase domain | endoplasmic reticulum-associated degradation assay | transacting mechanism P rotein p97, also called valosin-containing protein (VCP) in mammals and Cdc48 in yeast, is an essential and highly abundant type-II AAA ATPase, accounting for approximately 1% of the protein of the cell (1). The gene encoding p97 is one of the most conserved from archaebacteria to yeast and to humans (2-4). Protein p97 is involved in various important cellular activities including endoplasmic reticulum-associated degradation (ERAD), homotypic membrane fusion, programmed cell death, activation of B and T cells, the stress response, cell-cycle control and regulation of certain transcription factors (5-14). The diverse biological functions of p97 implicate it in a number of neurodegenerative diseases including Alzheimer's (15), Parkinson disease, and cancer (16).Protein p97 is a ring-shaped homohexameric protein. Each protomer consists of an unstructured C-terminal tail and three structured domains: a somewhat flexible N domain and two highly conserved AAAþ domains, termed the D1 and D2 domains (Fig. 1A) (17). The D1 domain is a degenerate ATPase domain that is responsible for hexameric-state stability (18), whereas the D2 domain is the major ATPase domain of p97 at physiological temperature (1). Protein p97 binds to different substrate-recruiting cofactors and substrates, resulting in various activities (16,(19)(20)(21). Structural studies of p97 in different nucleotide states showed that the protein undergoes conformation changes during nucleotide binding and hydrolysis [see review (17)]. In this manner, the free energy released from ATP hydrolysis may be utilized to drive the movement of its substrates from the lumen of the endoplasmic reticulum (ER) to the cytosol. However, it has been controversial how the ATP-hydrolysisinduced motion is transmitted through the length of the entire molecule; that is, from the D2 domain to the D1 domain and then to the distant N domain of p97 (22)(23)(24)(25)(26).The D1 and D2 domains of p97 are connected by a...

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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

Cited by 50 publications

References 54 publications

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

Interprotomer motion-transmission mechanism for the hexameric AAA ATPase p97

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