The process of apoptosis, in which cells undergo a two types of adaptor molecules help to define two types tightly controlled and coordinated death, proceeds via of death pathway, one involving death receptors and one the activation of caspase proteases that cleave key subinvolving the mitochondria (and cytochrome c release). strates. The activation or inactivation of these substrates Now there may be another. Sanchez et al.(1999) exis responsible for the “packaging” of the dying cell for amined the ability of polyglutamine repeats of 50 or clearance by phagocytes and is probably responsible more units to trigger caspase activation and apoptosis for actually killing the cell in many cases. How the protein cells transfected with the expression constructs. They ases become activated, then, is of central importance found that the cell death was blocked by a dominant to our understanding of cell life and death in a variety negative FADD (containing only the bit that normally ofphysiologicalandpathologicalsituations. Inthepaper binds to Fas) and by a dominant negative caspase-8. by Yuan and colleagues in this issue of Neuron (Sanchez Both of these proteins effectively localized to the large et al., 1999), the authors propose a novel pathway for polyglutamine aggregates in the cells, suggesting that the activation of caspases by proteins with extended procaspase-8 is similarly recruited. They showed that polyglutamine repeats of the sort associated with sevexpressionofapolyglutaminerepeatledtoendogenous eral neurodegenerative diseases, including Huntingcaspase-8 appearing in an insoluble fraction in the cell, ton’s disease, spinocerebellar ataxias, dentatorubral–presumably with the insoluble polyglutamine aggrepallidolyusian atrophy, and others (Perutz, 1999). They gates. Thus, recruitment of procaspase-8 to the polysuggest that polyglutamine repeat proteins assemble into insoluble aggregates containing one of the cas- glutamine aggregates may play a role in polyglutaminepases, which becomes activated, leading to apoptosis. induced apoptosis. In support of this, they found that a Although it is difficult to relate the in vitro studies to cell line lacking caspase-8 was resistant to polyglutain vivo disease, they show that this caspase, which is mine-induced apoptosis. normally soluble, partitions with an insoluble fraction in The model in panel C of the figure is consistent with extracts from the brains of several patients with Hunting- their observations. Polyglutamine repeats form aggreton’s disease. This raises the intriguing possibility that gates that bind to adaptor proteins such as FADD, which cytosolic aggregation of polyglutamine repeat proteins has itself been shown to form filamentous structures contributes to neurodegenerative disease via the re- in cells upon overexpression (Perez and White, 1998). cruitment, binding, and activation of caspases. FADD (and perhaps other adaptor molecules) recruits There are currently about a dozen human caspases procaspase-8, which transactivates. The ability of FADD identified, and only a subset of these are known to be DN to block binding and activation of procaspase-8 involved in apoptosis. All caspases are expressed as suggests that the binding of this adaptor (and any other single chain proenzymes with low proteolytic activity; relevant adaptor) is to a limited number of sites on the upon cleavage, these autoassemble into tetramers and polyglutamine filament. A procaspase-8 with a mutated increase their enzymatic activity about 100-fold (Ash- active site blocks caspase activation and apoptosis, kenazi and Dixit, 1998)(see figure). This cleavage can presumably because it complexes with endogenous occur …