Caspase Cleavage of Gene Products Associated with Triplet Expansion Disorders Generates Truncated Fragments Containing the Polyglutamine Tract

Wellington, Cheryl L.; Ellerby, Lisa M.; Hackam, Abigail S.; Margolis, Russell L.; Trifiro, Mark; Singaraja, Roshni R.; McCutcheon, Krista; Salvesen, Guy S.; Propp, Stephanie; Bromm, Michael; Rowland, Kathleen; Zhang, Taiqi; Rasper, Dita; Roy, Sophie; Thornberry, Nancy A.; Pinsky, Leonard; Kakizuka, Akira; Ross, Christopher A.; Nicholson, Donald W.; Bredesen, Dale E.; Hayden, Michael R.

doi:10.1074/jbc.273.15.9158

Cited by 517 publications

(380 citation statements)

References 36 publications

Supporting

Mentioning

367

Contrasting

Unclassified

Order By: Relevance

“…[26][27][28][29]43 In the present work, we demonstrate that specific caspases bind to Htt. The caspases that interact with Htt are enriched and activated in the vulnerable cell types in the striatum and cortex and therefore our work offers some potential insight into the selective neuronal cell death found in HD.…”

Section: Discussionmentioning

confidence: 85%

“…The recombinant caspase-3 and -7 was purified via a different method with higher specific activity and therefore accounts for the difference reported in our previous work. 29 (c) Radiolabeled caspase-resistant forms of Htt with 138 repeats (pRC-CMV3949-138) were incubated with the indicated recombinant caspases (B100 nM) or in cleavage buffer (uncleaved) in order to determine the site of caspase-2 cleavage. Densitometry of the caspase cleavage products of Htt indicate that caspase-2, -3, -6 cleaved Htt with similar efficacy and the caspase-resistant forms are resistant to cleavage relative to control.…”

Section: Hd Is Specifically Cleaved By Caspase-2 At Caspase Consensusmentioning

confidence: 99%

“…25 Despite the numerous studies in vitro and in vivo supporting a correlation between Htt length and toxicity, little is known about how cleavage events may be initiated or how the proteolytic processing of Htt or other polyglutamine disease proteins is regulated. [26][27][28][29] Cell-type-dependent cleavage by specific caspases or other proteases may explain some of the selective neurodegeneration seen in these diseases. Evidence for region-specific cleavage of Htt in vivo comes from studies of YAC transgenic mice expressing mutant full-length huntingtin (YAC72).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

View full text Add to dashboard Cite

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Hd Is Specifically Cleaved By Caspase-2 At Caspase Consensusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Cell extracts were prepared as described by Wellington et al [20]. Cells were seeded in 6-well plates (250,000 cells/well).…”

Section: Caspase-3 Activity Assaymentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

View full text Add to dashboard Cite

Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis.In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO 2 but participates in the protective effect of hypoxia against etoposide-induced apoptosis.Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.

show abstract

“…Nevertheless, the fact that caspase-1 can cleave both mutant and wild-type huntingtin in vitro (Wellington et al, 1998) raised the question whether inhibition of this caspase could interfere with the progression of the disease. Therefore, Ona et al (1999) crossbred R6/2 mice with transgenic mice expressing a dominant-negative mutant of caspase-1 in the brain (Ona et al, 1999).…”

Section: Caspase Inhibitionmentioning

confidence: 99%

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Gil

Rego

2009

Brain Research Reviews

View full text Add to dashboard Cite

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

show abstract

Caspase Cleavage of Gene Products Associated with Triplet Expansion Disorders Generates Truncated Fragments Containing the Polyglutamine Tract

Cited by 517 publications

References 36 publications

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Contact Info

Product

Resources

About