Caspase-8 Is Required for Cell Death Induced by Expanded Polyglutamine Repeats

Abstract

We show here that caspase-8 is required for the death of primary rat neurons induced by an expanded polyglutamine repeat (Q79). Expression of Q79 recruited and activated caspase-8. Inhibition of caspase-8 blocked polyglutamine-induced cell death. Coexpression of Q79 with the caspase inhibitor CrmA, a dominant-negative mutant of FADD (FADD DN), Bcl-2, or Bcl-xL, but not an N-terminally tagged Bcl-xL, prevented the recruitment of caspase-8 and inhibited polyglutamine-induced cell death. Furthermore, Western blot analysis revealed the presence of activated caspase-8 in the insoluble fraction of affected brain regions from Huntington's disease (HD) patients but not in those from neurologically unremarkable controls, suggesting the relocation and activation of caspase-8 during the pathogenesis of HD. These results suggest an essential role of caspase-8 in HD-related neural degenerative diseases.

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

“…This finding may also explain the apparent differences between the report that a polyglutamine tract demonstrates interaction with caspase-8 38 and our failure to identify caspase-8 interaction with fulllength Htt (or to identify caspase-8 requirement in Htt-induced striatal neuronal cell death).…”

“…Our results differ from an earlier report using primary culture because we use the full-length Htt construct while they used a Htt-derived fragment mostly composed of polyglutamine repeats. 38 Using a primary culture model where full-length Htt is expressed is more relevant for evaluating the early events in HD disease pathogenesis and proteolysis. Next, we examined whether coexpression of catalytically inactive forms of caspase-2 (C303A), caspase-3 (C163A), caspase-6 (C163A), caspase-7 (C186A), caspase-8 (C360A), or caspase-9 (C287A) inhibit cell death induced by Htt138 in striatal neurons.…”

Apoptosis in health and disease and modulation of apoptosis for therapy: An overview

“…Huntington's disease (HD) results from an aberrant expansion of CAG repeats, which is translated into a polyglutamine repeat in the Huntingtin protein (Htt), which is a substrate for caspase-3. Cytosolic aggregates of polyglutamine repeat proteins may recruit procaspase 8, resulting in the activation of caspase -8 (48). Thus caspases play an important role in mediating cell death in human neurodegenerative diseases.Amyotrophic lateral sclerosis (ALS) is associated with death of motor neurons in the spinal cord and brain due to mutations in the gene encoding CuZnSoD .…”

Caspases on the brain

“…Examination of post-mortem tissue has implicated caspases in multiple neurodegenerative diseases. Cleaved caspases have been detected in AD (caspases 3, 6, and 9; Chan et al, 1999;LeBlanc et al, 1999;Stadelmann et al, 1999;Lu et al, 2000), in ALS (caspases 1 and 3; Pasinelli et al, 1998), in Parkinson's disease (PD; caspases 3, 8, and 9; Anglade et al, 1997;Jeon et al, 1999;Viswanath et al, 2001), in ischemia (caspases 1 and 3; Love et al, 2000), and Huntington's disease (HD; caspases 1 and 8; Sanchez et al, 1999). Such findings are correlative, in that it is almost impossible to identify definitively causal factors of disease in end-stage brain.…”

“…In PD models, both the extrinsic and the intrinsic pathways have been implicated in studies using pseudosusbstrate inhibitors (Viswanath et al, 2001) and immunocytochemistry of cleaved caspase 3 (Jeon et al, 1999). For HD, the extrinsic pathway has been proposed to be necessary (Sanchez et al, 1999). Overexpression of dominantnegative caspase 1 delays disease in the mouse model of ALS (Friedlander et al, 1997) and in a model of ischemia (Friedlander et al, 1997).…”