Copyright

Annu. Rev. Neurosci. 2000. 23:7387 2000 by Annual Reviews. All rights reserved

APOPTOSIS IN NEURAL DEVELOPMENT AND DISEASE

Deepak Nijhawan, Narimon Honarpour, and Xiaodong Wang
Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235; e-mail: nijhawan.deepak@tumora.swmed.edu, nhonarpour@hotmail.com, xwang@biochem.swmed.edu

Key Words caspase, Bcl-2, cytochrome c, Apaf-1, neurodegenerative

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

Abstract Cell death via apoptosis is a prominent feature in mammalian neural development. Recent studies into the basic mechanism of apoptosis have revealed biochemical pathways that control and execute apoptosis in mammalian cells. Protein factors in these pathways play important roles during development in regulating the balance between neuronal life and death. Additionally, mounting evidence indicates such pathways may also be activated during several neurodegenerative diseases, resulting in improper loss of neurons.

INTRODUCTION
In 1972, Kerr et al coined the term apoptosis, after the Greek word meaning leaves falling from a tree, to describe an intrinsic cell suicide program involved in the normal turnover of hepatocytes (Kerr et al 1972). Cell morphologic manifestations of apoptosis include condensation of cell contents, nuclear membrane breakdown, and the formation of apoptotic bodies that are small membrane-bound vesicles phagocytosed by neighboring cells. Molecular components of the apoptotic pathway were rst described in two important studies. Genetic studies in Caenorhabditis elegans revealed three genes, ced3, ced4, and ced9, that specically function in a pathway that controls developmental specic cell death (Ellis et al 1991). Second, Bcl-2, a human oncogene overexpressed in follicular lymphoma, was found to inuence cell apoptotic response (Adams & Cory 1998). These discoveries ignited an explosion of research into apoptosis that in the past decade has unveiled a complex, yet cohesive, picture of this intrinsic cell suicide program. Apoptotic signals, both intracellular and extracellular, converge to activate a group of apoptotic-specic cysteine proteases termed caspases that cleave their substrates with signature specicity after aspartic acid residues (Figure 1; see color insert) (Thornberry & Lazebnik 1998). Chromatin condensation, DNA
0147006X/00/03010073$12.00

73

74

NIJHAWAN

HONARPOUR

WANG

fragmentation into nucleosomal fragments, nuclear membrane breakdown, and the formation of apoptotic bodies are direct consequences of caspase activity. In this review article, we focus on current understanding of biochemical pathways upstream and downstream of caspase activation in mammalian neuronal development and human neurological diseases. The review is divided into three sections: (a) a current description of caspase activation and DNA fragmentation in the apoptotic pathway, (b) the role of pro- and anti-apoptotic proteins in neural development, and (c) evidence implicating apoptosis in neurodegenerative disease.

BIOCHEMICAL MECHANISMS OF APOPTOSIS DNA Fragmentation and Chromatin Condensation During Apoptosis
Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

The fragmentation of DNA into nucleosomal fragments was one of the rst identied cellular features of apoptosis, and it is commonly used as a biochemical marker for apoptosis (Wyllie 1980). In vivo, nucleosomal DNA fragmentation is assayed by the TUNEL (TdT-mediated dUTP-biotin nick end labeling) stain: Free DNA ends are end labeled with biotinylated poly-dUTP by terminal deoxytransferase and then stained using avidin-conjugated peroxidase (Gavrieli et al 1992). DNA fragmentation is mediated by a heterodimeric factor of 40 and 45 kDa, respectively, in humans [DNA fragmentation factor (DFF) 40 and 45] and in mice [caspase activated DNase (CAD) and inhibitor of caspase-activated DNase (ICAD)] (Liu et al 1997, 1998; Enari et al 1998). DFF40/CAD and DFF45/ICAD are encoded by novel genes and do not share sequence homology with other proteins with known functions. In apoptotic cells, DFF45, which has two caspase cleavage sites, is cleaved into three smaller fragments. Cleaved DFF45 dissociates from DFF40, inducing oligomerization of DFF40 into a large protein complex that has DNase activty (Liu et al 1999). DFF activity can only be reconstituted by coexpressing the two subunits together (Liu et al 1998, Enari et al 1998). When expressed alone, DFF40 has lower expression and no DNase activity, which suggests that DFF45 functions as a specic molecular chaperone important for DFF40 activation and synthesis (Liu et al 1998). Unlike other DNases, DFF40 is signicantly stimulated by internucleosomal, chromatin-associated proteins such as high mobility group (HMG)-1, -2, and -14 and histone H1 but not core histones (Liu et al 1998, 1999). HMGs and histone H1 may target DFF40 to the internucleosomal linker region, resulting in the exquisite pattern of internucleosomal DNA fragmentation commonly detected during apoptosis. The multimeric nature of the active DFF40 may also contribute to apoptotic chromatin condensation by pulling cleaved nucleosomal fragments together. After treatment with active DFF40, nuclei stained with a DNA dye exhibit bright particles, an apoptotic hallmark indicative of chromatin condensation (Liu et al 1998). Thymocytes and

NEURAL APOPTOSIS

75

splenocytes from mice decient in ICAD die by apoptosis but fail to condense chromatin or fragment DNA (Zhang et al 1998). ICAD null mice develop normally and are fertile, indicating that DNA fragmentation and chromatin condensation during apoptosis is not essential for normal development of a mouse (Zhang et al 1998).

Caspase Activation Pathways

In living cells, caspases exist as inactive zymogens that, like DFF, are activated by proteolytic cleavage (Thornberry & Lazebnik 1998). There are two relatively well-studied pathways that lead to caspase activation (Figure 1). One pathway involves death receptors, such as Fas, and a tumor necrosis factor (TNF) receptor at the cell surface, leading to the activation of caspase-8 intracellularly (Ashkenazi & Dixit 1998). Fas ligand and TNF, which usually exist as trimers, bind and activate their receptors by inducing receptor trimerization (Nagata 1997). Activated receptors recruit adaptor molecules such as FADD/MORT1 (Fas-associating protein with death domain), which recruit procaspase-8 to the receptor complex, where it undergoes autocatalytic activation (Boldin et al 1995, 1996; Chinnaiyan et al 1995; Muzio et al 1996; Srinivasula et al 1996). Activated caspase-8 will cleave and activate other downstream caspases, such as caspase-3, caspase-6, and caspase-7, constituting the main caspase activity of apoptotic cells (Boldin et al 1996, Muzio et al 1996, Srinivasula et al 1996). Another means of caspase activation is through the release of cytochrome c from the mitochondria. Cytochrome c is a 13-kDa soluble electron transfer protein exclusively located in the mitochondrial intermembrane space. During apoptosis, however, the outer membrane of mitochondria becomes permeable to cytochrome c (Liu et al 1996), which binds to Apaf-1. Apaf-1 is a 130-kDa cytosolic monomer consisting of three distinctive domains: a caspase recruitment domain, CED4 homologous domain, and a series of WD40 repeats (Zou et al 1997). On induction of apoptosis, Apaf-1 forms a multimeric complex with cytochrome c (Li et al 1997, Zou et al 1999). Apaf-1/ cytochrome c complexes are sufcient to recruit and activate procaspase-9. Activated caspase-9 released from the complex activates downstream caspases such as caspase-3, caspase-6, and caspase-7.

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

Regulation of Cytochrome c Release by the Bcl-2 Family of Proteins

A major regulatory step for caspase activation is at the level of cytochrome c release from mitochondria to cytosol. Cytochrome c release not only initiates caspase activation by activating Apaf-1, it also breaks the electron transfer chain resulting in reduced energy generation and more reactive oxygen species due to incomplete reduction of atomic oxygen (Reed 1997). The release of cytochrome c is regulated by the Bcl-2 family of proteins, including anti-apoptotic members

76

NIJHAWAN

HONARPOUR

WANG

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

Bcl-2 and Bcl-xL and pro-apoptotic Bak, Bim, Bad, and Bax (Adams & Cory 1998). Overexpression of anti-apoptotic Bcl-2, or its close homologue Bcl-xL, blocks cytochrome c release induced by a variety of apoptotic stimuli (Kim et al 1997, Kluck et al 1997, Yang et al 1997). In contrast, Bax, Bak, and Bid have been shown to directly cause cytochrome c release both in vivo and in vitro (Jurgensmeier et al 1998, Kuwana et al 1998, Li et al 1998, Luo et al 1998, Rosse et al 1998). The mechanism of cytochrome c release and its regulation by the Bcl-2 family of proteins is not known. One possibility is that changes in mitochondrial membrane permeability induce mitochondrial swelling, causing outer membrane rupture (Kroemer et al 1997; Vander Heiden et al 1997, 1999). On the other hand, increases in outer membrane permeability may occur independent of swelling. Intrinsic or extrinsic death signals may be transmitted to the mitochondria by the translocation of pro-apoptotic Bcl-2 family members to the mitochondria from different cellular compartments. Extracellular death signals such as Fas ligand or TNF activate caspase-8 intracellularly. Activated caspase-8 cleaves and activates Bid, which translocates to the mitochondria and induces cytochrome c release, amplifying the caspase activation signal (Li et al 1998, Luo et al 1998). Extracellular survival signals inhibit apoptosis by activating the phosphotidylinositol3 kinase/Akt pathway, leading to Bad phosphorylation. Phosphorylated Bad binds 143-3 protein and is sequestered in the cytoplasm, whereas dephosphorylated Bad translocates to the mitochondria (Zha et al 1996). Conversely, Ca2 may induce apoptosis by activating the calcineurin-dependent phosphatase that dephosphorylates Bad (Wang et al 1999). Other intrinsic death signals may regulate Bim translocation. In normal living cells, Bim, a pro-apoptotic Bcl-2 family member, binds to LC8, a cytoskeletal component. After cells are induced to die by apoptosis, the Bim/LC8 complex dissociates from the cytoskeleton and translocates to the mitochondria (Puthalakath et al 1999). Bax has also been shown to translocate from the cytoplasm to the mitochondria during apoptosis (Wolter et al 1997). Apoptotic signals may activate the translocation of these factors to the mitochondria, which then trigger cytochrome c release, inducing caspase activation.

APOPTOSIS IN NEURAL DEVELOPMENT

Apoptosis occurs throughout the nervous system in neuron, glial, and neural progenitor cells. It is estimated that at least half of the original cell population is eliminated as a result of apoptosis in the developing nervous system (Oppenheim 1981, Burek & Oppenheim 1999). The potential role of apoptosis during neural development includes optimization of synaptic connections, removal of unnecessary neurons, and pattern formation (Burek & Oppenheim 1999). A neurons chance for survival during development is believed to directly depend on the extent of its connections to a postsynaptic target, which suggests that neurons are

NEURAL APOPTOSIS

77

initially overproduced and then compete for target-derived neurotrophic factors (Cowan et al 1984). Neurons also receive trophic support from glial cells, presynaptic cells, and steroid hormones (Lindsay 1979, Okado & Oppenheim 1984, Nordeen et al 1985, Linden 1994). How do such developmental signals as limited trophic factor support induce apoptosis during neural development? Neurotrophin mediated survival is linked to the regulation of cytochrome c release and caspase activation. Following NGF withdrawal from sympathetic neurons, cytochrome c is released from the mitochondria to the cytosol, and apoptosis ensues (Deshmukh & Johnson 1998). In Bax-decient sympathetic neurons, however, there is a delay in cytochrome c release when NGF is removed, implying that Bax catalyzes the release of cytochrome c on withdrawal of nerve growth factor (NGF) (Easton et al 1997, Deshmukh & Johnson 1998, Neame et al 1998). The balance between pro- and anti-apoptotic Bcl-2 family members is important for neural survival during development. Mice decient in Bcl-xL, which is widely expressed throughout the developing nervous system, die at embryonic day 13 (E13) with extensive apoptotsis in the postmitotic, differentiating immature neurons of the brain, spinal cord, and dorsal root ganglia (Motoyama et al 1995). Bcl-2 is widely expressed in the developing nervous system but only persists at high levels in the adult peripheral nervous system (Merry et al 1994). Postnatal Bcl-2 knockout mice have signicant degeneration of the facial motor neurons, dorsal root ganglion (L3) sensory neurons, and sympathetic neurons in the superior cervical ganglion, indicating that Bcl-2 is necessary for peripheral nervous system survival postnataly but not for neuronal survival during central nervous system development (Michaelidis et al 1996). Consistently, ectopic expression of Bcl-2 in neurons results in brain hypertrophy, with more neurons in the mesencephalic nucleus of the trigeminal nerve, the facial nucleus, the fth lumbar dorsal root ganglion, and the retinal ganglion cell layer (Martinou et al 1994, Farlie et al 1995). Deletion of Bax, which is predominantly expressed in the neonatal cortex, superior cervical ganglion, and facial motor nucleus, results in a 51% increase in facial motor neurons and yields 2.5-fold more superior cervical ganglion neurons (Deckwerth et al 1996, Vekrellis et al 1997). Notably, mice heterozygous for Bax disruption possess more neurons in the facial motor nucleus and superior cervical ganglion than do wild-type mice but fewer than Bax null mice, indicative of a gene dosing effect (Deckwerth et al 1996). Alterations in Bcl-2 family members also regulate cell death following axotomy. Bax, but not Bcl-2, is important for mediating axotomy-induced apoptosis. Motor neurons do not survive after axotomy in Bcl-2decient or wild-type mice; however, in response to axotomy, 86% of the facial motor neurons in neonatal Bax-decient mice survive (Deckwerth et al 1996). Following axotomy, overexpression of Bcl-2 reduces death probably by tilting the balance of pro- and antiapoptotic Bcl-2 family members in favor of survival (Allsopp et al 1993, Dubois-Dauphin et al 1994, Farlie et al 1995, Michaelidis et al 1996). Target-

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

78

NIJHAWAN

HONARPOUR

WANG

derived trophic factors may promote survival by inuencing Bax activity, potentially preventing its translocation from the cytosol to the mitochondria. The essential role of apoptosis in neural development is dramatically illustrated by mice decient in Apaf-1, caspase-9, and caspase-3 (Kuida et al 1996, Cecconi et al 1998, Hakem et al 1998, Kuida et al 1998, Yoshida et al 1998). Despite their ubiquitous expression, pathology resulting from the disruption of these genes mostly affects the developing brain and is lethal. In all three cases, knockout mice have prominent protrusions of the forebrain with exencephaly (Figure 2; see color insert). These mice also possess craniofacial malformations and ventriclular obstruction by supernumerary mitotic and differentiating neurons (Cecconi et al 1998, Yoshida et al 1998). These studies further support in vitro data describing a linear cytochrome cdependent caspase activation pathway: No activated caspase-3 is detected in the brains of Apaf-1 null mice (Cecconi et al 1998).

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

APOPTOSIS IN NEURODEGENERATIVE DISEASE

If neurons die by apoptosis during development, could the same pathways be activated in neurodegenerative disease? Recently, investigation into neurodegenerative disease has focused on this question in the hope that apoptosis may ultimately serve as a valuable therapeutic target for several currently untreatable diseases. We focus on three well-studied disorders with strong implications of apoptosis in neurodegeneration: Alzheimers disease, Huntingtons disease, and amyotrophic lateral sclerosis. All these diseases have the following in common: (a) a familial form of the disease with a mendelian inheritance pattern, (b) selective degeneration of particular neuronal subtypes, and (c) disease-associated cellular or extracellular aggregates.

Alzheimers Disease
Alzheimer disease (AD) is the most common cause of dementia among the elderly. AD is the result of damage to selective neuronal circuits in the neocortex, hippocampus, and basal forebrain cholinergic system. Some forms of AD, primarily early onset, are familial (FAD) and show an autosomal dominant inheritance pattern. Missense mutations in three genes, amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2) are associated with FAD (Price & Sisodia 1998). In AD, postmortem histopathology reveals either one or both of the following: (a) dystrophic neurites and intracellular neurobrillary tangles, which are composed of the tau protein (Goedert et al 1996); (b) extracellular senile plaques composed of the 42- to 43-amino acid b-amyloid peptide (Ab), which is a minor proteolytic product of APP. Ab is neurotoxic to primary neuronal cells, and overexpression of the Ab peptide intracellularly in transgenic mice causes neurodegeneration. Additionally, transgenic mice overexpressing FAD mutant APP (V717F), wild-type PS1, or both develop senile plaques composed

NEURAL APOPTOSIS

79

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

of Ab aggregates and dystrophic neurites similar to the histopathology seen in AD patients (Games et al 1995, Masliah et al 1996, Holcomb et al 1998). Degenerating neurons in APP V717F b-amyloid mice show chromatin segmentation and condensation and increased TUNEL staining, which suggests an apoptotic death. COS or F11 cells (a hybrid of a primary rat dorsal root ganglion neuron and a mouse neuroblastoma cell line) overexpressing FAD mutant APP (V642I, V642F, or V642G) have increased DNA fragmentation and TUNEL staining, i.e. inhibited by Bcl-2 coexpression (Yamatsuji et al 1996a,b). In a similar manner, wild-type PS2, FAD mutant PS2 (N141I), or PS1 (A246E) overexpression sensitizes PC12 cells to apoptosis after b-amyloid treatment or trophic factor withdrawal (Deng et al 1996, Wolozin et al 1996). In contrast, using a herpes simplex virus, Bursztajn and colleagues (1998) found that overexpression of PS1 or PS1 (A246E) in primary mouse cortical culture does not enhance apoptosis, which suggests that the apoptogenic effects of mutant presenlin in culture are cell type specic. The importance of apoptosis in AD pathogenesis is supported by evidence describing increased TUNEL staining and activated caspases in postmortem analysis of AD brain (Dragunow et al 1995, Lassmann et al 1995, Smale et al 1995, Bancher et al 1996, Gervais et al 1999). Little is known about which molecules mediate AD-associated apoptosis. One important player might be Par-4, which was rst identied in prostate cancer cells undergoing apoptosis (Sells et al 1994, 1997). Par-4 is expressed at high levels in regions of the brain affected by AD, including the hippocampus. Apoptosis in hippocampal neurons exposed to b-amyloid in culture requires Par-4 up-regulation because neurons transfected with Par-4 antisense message survive treatment (Guo et al 1998).

Huntingtons Disease
Huntingtons disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant pattern of inheritance characterized by hyperkinetic involuntary movements, slowing of voluntary movements, and cognitive impairment (Harper 1991). The major pathological change in HD patients is the selective degeneration of the cortex and striatum due to a CAG triplet expansion in the rst exon of huntingtin, which forms a polyglutamine expansion in a protein of approximately 350 kDa (Huntingtons Dis. Collab. Res. Group 1993). Normal individuals have between 10 and 35 repeats whereas HD patients have from 37 to 121. Immunohistological analysis of brains from HD patients and the HD mouse model revealed neuronal nuclear inclusions throughout the brain that are immunoreactive with anti-huntingtin and anti-ubiquitin (Davies et al 1997, DiFiglia et al 1997, Scherzinger et al 1997, Reddy et al 1998). Huntingtin shares no signicant sequence homology with any other known genes and is widely expressed throughout the brain in regions both affected and spared during the course of HD. Mice decient in huntingtin die between E8.5

80

NIJHAWAN

HONARPOUR

WANG

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

and E10.5 (Duyao et al 1995, Nasir et al 1995, Zeitlin et al 1995). In huntingtin null mice, embryonic ectodermal cells exhibit increased apoptosis, which suggests an anti-apoptotic role for huntingtin. Transgene expression of full-length huntingtin cDNA with 48 or 89 but not 16 CAG repeats exhibits a progressive neurological phenotype recapitulating many of the clinical features of HD (Reddy et al 1998). Neuropathological analysis revealed prominent neuronal loss in the striata, hippocampus, thalamus, and cerebral cortex whereas purkinje cells remained unaffected, demonstrating selective neuronal loss. These mice also have intranuclear neuronal inclusions that directly correlate with disease severity. Finally, neurodegenerative regions of the brain show increased TUNEL staining compared with age-matched wild-type controls, which is suggestive of apoptotic death. Recently, debate has focused on the role of nuclear inclusions in neurodegeneration and HD pathogenesis. Saudou et al (1998) demonstrate that mutant huntingtin selectively kills striatal but not purkinje neurons in culture by apoptosis. Cell death was dependent on nuclear localization but was not associated with intranuclear inclusions. In fact, they propose that the formation of inclusions might be a form of cellular defense because conditions that suppress inclusion formation result in increased apoptosis. On the other hand, Sanchez et al (1999) show that FADD is recruited to and caspase-8 is activated on inclusions, which suggests that inclusions composed of polyglutamine repeats induce apoptosis by catalyzing caspase activation. These authors induce apoptosis in primary cerebellar and striatal neurons by overexpressing a construct containing green uorescent protein and an expanded CAG repeat. Cotransfection with a dominant negative form of FADD inhibits apoptosis and reduces recruitment of caspase-8 to inclusions. Furthermore, they identied activated caspase-8 in the insoluble protein fraction of postmortem HD brain, which suggests that activated caspase8 colocalizes with inclusions. Cell culture studies and in vivo studies of mouse models suggest that cell death induced by mutant huntingtin involves apoptosis. The role of inclusions in HD-related apoptosis is still unclear. However, if neurons die apoptotically because of inclusion-induced caspase activation, then drugs that inhibit inclusion formation or inhibit caspase activation would be of potential therapeutic benet.

Amyotrophic Lateral Sclerosis

Patients with amyotrophic lateral sclerosis (ALS) suffer from muscle atrophy and fatal paralysis as a result of selective degeneration of both upper and lower motor neurons. Some 10% of ALS cases are familial (FALS), with an autosomal dominant pattern of inheritance (Brown 1995). Some 20% of FALS cases are due to mutations in the ubiquitously expressed cytoplasmic Cu/Zn superoxide dismutase (SOD1), which protects cells from oxidative damage induced by the superoxide anion (Deng et al 1993, Rosen et al 1993). Transgenic mice overexpressing FALS mutant SOD1 exhibit a phenotype similar to FALS, including selective loss of

NEURAL APOPTOSIS

81

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

upper and lower motor neurons, muscle atrophy, and paralysis (Gurney et al 1994, Dal Canto & Gurney 1995, Ripps et al 1995, Bruijn et al 1997). FALS patients with SOD1 mutations and SOD1 mutant mice have neuronal and astrocytic cytoplasmic inclusions that are immunoreactive for SOD1 (Kato et al 1996, 1999; Shibata et al 1996; Bruijn et al 1998). In SOD1 mutant mice, inclusions appear before disease onset and increase in abundance during the course of disease (Bruijn et al 1998). In FALS, mutant SOD1 may adopt a novel gain of function that is selectively toxic to motor neurons. Bcl-2 overexpression in neurons of ALS mice signicantly delays the onset but not the duration of disease (Kostic et al 1997). In contrast, overexpression of dominant negative caspase-1 (DNcaspase-1) in neurons delays the duration but not the onset of disease (Friedlander et al 1997). These data may be explained by the differing effects of Bcl-2 and DNcaspase-1 on apoptosis; upstream, Bcl-2 inhibits cytochrome c release, and downstream, DNcaspase-1 inhibits caspase activity. Cytochrome c release may be the trigger for the toxic effect of mutant SOD1, and thus inhibiting release would delay onset. However, once cytochrome c is released and caspases are activated, the cell is committed to die, so caspase inhibition will only delay the course of disease. Although these studies provide in vivo evidence that motor neurons in ALS mice die via apoptosis, they should be considered with caution for the following reasons: (a) Mice overexpressing Bcl-2 in neurons possess more neurons than do normal mice, which might explain the effect on disease course (Martinou et al 1994), and (b) DN-caspase-1 may not inhibit other caspases, which presumably would also be activated. The toxic effects of mutant SOD1 have also been shown in culture. Using an adenoviral transducing system, Ghadge et al (1997) showed that two different SOD1 mutations are selectively toxic to PC12 cells, primary sympathetic, and hippocampal pyramidal mouse neurons but not astrocytes. Dying PC12 cells or primary neurons exhibit characteristics of an apoptotic death, including shrunken cell bodies, increased TUNEL staining, and chromatin condensation. Moreover, PC12 cell death is inhibited by caspase inhibitors and Bcl-2 contransfection.

CONCLUSION
Much evidence has been gathered implicating apoptosis in neurodegenerative disease. Although these studies provide hope that the apoptotic program is an effective therapeutic target, important questions about how disease induces apoptosis remain: Is apoptosis the cells reaction to a permanent neuronal insult inicted by disease or is the disease directly involved in activating the apoptotic program? In the latter case, anti-apoptotic agents such as caspase inhibitors could be used to inhibit cell death and preserve cellular integrity. In the former case, however, caspase inhibitors would be less benecial because cellular integrity would already be compromised by disease.

82

NIJHAWAN

HONARPOUR

WANG

All three of the diseases reviewed are associated with intracelluar or extracellular protein aggregation (Kakizuka 1998). Recent reports suggest that neurodegeneration may be the result of protein aggregation that directly activates caspases and induces apoptosis. It is difcult to imagine how mutated disease genes might directly activate the apoptotic program, because disease onset occurs in later life. However, the formation of aggregates later in life might serve as the rate-limiting step in triggering the degenerative disease process. The recruitment of apoptogenic proteins to protein aggregates may activate apoptotic pathways because oligomerization steps are required for the formation of active multimeric complexes in FADD/caspase-8, Apaf-1/caspase-9, and DFF pathways. In such cases, drugs that prevent aggregate formation or inhibit caspase activation might be effective therapies. ACKNOWLEDGMENTS
Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

We thank Drs. Razqallah Hakem and Tak Mak for pictures of wild-type, Apaf1, caspase-9, and caspase-3 mutant mice. We thank Dr. Roger Rosenberg for suggestions and critical reading of the manuscript.
Visit the Annual Reviews home page at www.AnnualReviews.org.

LITERATURE CITED
Adams JM, Cory S. 1998. The Bcl-2 protein family: arbiters of cell survival. Science 281:132226 Allsopp TE, Wyatt S, Paterson HF, Davies AM. 1993. The proto-oncogene bcl-2 can selectively rescue neurotrophic factordependent neurons from apoptosis. Cell 73:295307 Ashkenazi A, Dixit VM. 1998. Death receptors: signaling and modulation. Science 281:13058 Bancher C, Leitner H, Jellinger K, Eder H, Setinek U, et al. 1996. On the relationship between measles virus and Alzheimer neurobrillary tangles in subacute sclerosing panencephalitis. Neurobiol. Aging 17:527 33 Boldin MP, Goncharov TM, Goltsev YV, Wallach D. 1996. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85:80315 Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D. 1995. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J. Biol. Chem. 270:779598 Brown RH Jr. 1995. Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice. Cell 80:68792 Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, et al. 1997. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:32738 Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, et al. 1998. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281:185154 Burek M, Oppenheim R. 1999. Cellular interactions that regulate programmed cell death

NEURAL APOPTOSIS in the developing vertebrate nervous system. In Cell Death and Disease of the Nervous System, ed. V Koliatsos, R Ratan, 1:14580. Totowa: Humana Bursztajn S, DeSouza R, McPhie DL, Berman SA, Shioi J, et al. 1998. Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis. J. Neurosci. 18:979099 Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P. 1998. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94:72737 Chinnaiyan AM, ORourke K, Tewari M, Dixit VM. 1995. FADD, a novel death domaincontaining protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:50512 Cowan WM, Fawcett JW, OLeary DD, Staneld BB. 1984. Regressive events in neurogenesis. Science 225:125865 Dal Canto MC, Gurney ME. 1995. Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res. 676:2540 Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, et al. 1997. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:53748 Deckwerth TL, Elliott JL, Knudson CM, Johnson EM Jr, Snider WD, Korsmeyer SJ. 1996. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17:40111 Deng G, Pike CJ, Cotman CW. 1996. Alzheimer-associated presenilin-2 confers increased sensitivity to apoptosis in PC12 cells. FEBS Lett. 397:5054 Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, et al. 1993. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 261:1047 51

83

Deshmukh M, Johnson EM Jr. 1998. Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron 21:695705 DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, et al. 1997. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:199093 Dragunow M, Faull RL, Lawlor P, Beilharz EJ, Singleton K, et al. 1995. In situ evidence for DNA fragmentation in Huntingtons disease striatum and Alzheimers disease temporal lobes. NeuroReport 6:105357 Dubois-Dauphin M, Frankowski H, Tsujimoto Y, Huarte J, Martinou JC. 1994. Neonatal motoneurons overexpressing the bcl-2 protooncogene in transgenic mice are protected from axotomy-induced cell death. Proc. Natl. Acad. Sci. USA 91:330913 Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, et al. 1995. Inactivation of the mouse Huntingtons disease gene homolog Hdh. Science 269:40710 Easton RM, Deckwerth TL, Parsadanian AS, Johnson EM Jr. 1997. Analysis of the mechanism of loss of trophic factor dependence associated with neuronal maturation: a phenotype indistinguishable from Bax deletion. J. Neurosci. 17:965666 Ellis RE, Yuan JY, Horvitz HR. 1991. Mechanisms and functions of cell death. Annu. Rev. Cell. Biol. 7:66398 Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. 1998. A caspaseactivated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:4350; Erratum. 1998. Nature 393:396 Farlie PG, Dringen R, Rees SM, Kannourakis G, Bernard O. 1995. bcl-2 transgene expression can protect neurons against developmental and induced cell death. Proc. Natl. Acad. Sci. USA 92:4397401 Friedlander RM, Brown RH, Gagliardini V, Wang J, Yuan J. 1997. Inhibition of ICE slows ALS in mice. Nature 388:31; Erratum. 1998. Nature 392:560

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

84

NIJHAWAN

HONARPOUR

WANG protein and presenilin 1 transgenes. Nat. Med. 4:97100 Huntingtons Dis. Collab. Res. Group. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons disease chromosomes. Cell 72:97183 Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC. 1998. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl. Acad. Sci. USA 95:49975002 Kakizuka A. 1998. Protein precipitation: a common etiology in neurodegenerative disorders? Trends Genet. 14:396402 Kato S, Horiuchi S, Nakashima K, Hirano A, Shibata N, et al. 1999. Astrocytic hyaline inclusions contain advanced glycation endproducts in familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutation: immunohistochemical and immunoelectron microscopical analyses. Acta Neuropathol. 97:26066 Kato S, Shimoda M, Watanabe Y, Nakashima K, Takahashi K, Ohama E. 1996. Familial amyotrophic lateral sclerosis with a two base pair deletion in superoxide dismutase 1: gene multisystem degeneration with intracytoplasmic hyaline inclusions in astrocytes. J. Neuropathol. Exp. Neurol. 55:1089101 Kerr JF, Wyllie AH, Currie AR. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26:23957 Kim CN, Wang X, Huang Y, Ibrado AM, Liu L, et al. 1997. Overexpression of Bcl-X(L) inhibits Ara-C-induced mitochondrial loss of cytochrome c and other perturbations that activate the molecular cascade of apoptosis. Cancer Res. 57:311520 Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. 1997. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:113236 Kostic V, Jackson-Lewis V, de Bilbao F, Dubois-Dauphin M, Przedborski S. 1997.

Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, et al. 1995. Alzheimertype neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:52327 Gavrieli Y, Sherman Y, Ben-Sasson SA. 1992. Identication of programmed cell death in situ via specic labeling of nuclear DNA fragmentation. J. Cell Biol. 119:493501 Gervais F, Xu D, Robertson GS, Vaillancourt J, Zhu Y, et al. 1999. Involvement of caspases in proteolytic cleavage of Alzheimers amyloid-b precursor protein and amyloidogenic b peptide formation. Cell 97:395406 Ghadge GD, Lee JP, Bindokas VP, Jordan J, Ma L, et al. 1997. Mutant superoxide dismutase-1-linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection. J. Neurosci. 17:875666 Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA. 1996. Assembly of microtubule-associated protein tau into Alzheimer-like laments induced by sulphated glycosaminoglycans. Nature 383:55053 Guo Q, Fu W, Xie J, Luo H, Sells SF, et al. 1998. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat. Med. 4:957 62 Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, et al. 1994. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:177275; Erratum. 1995. Science 269:149 Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, et al. 1998. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:33952 Harper P. 1991. Huntingtons Disease, Vol. 22. London: Saunders. 438 pp. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, et al. 1998. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

NEURAL APOPTOSIS Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science 277:55962 Kroemer G, Zamzami N, Susin SA. 1997. Mitochondrial control of apoptosis. Immunol. Today 18:4451 Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, et al. 1998. Reduced apoptosis and cytochrome cmediated caspase activation in mice lacking caspase 9. Cell 94:32537 Kuida K, Zheng TS, Na S, Kuan C, Yang D, et al. 1996. Decreased apoptosis in the brain and premature lethality in CPP32-decient mice. Nature 384:36872 Kuwana T, Smith JJ, Muzio M, Dixit V, Newmeyer DD, Kornbluth S. 1998. Apoptosis induction by caspase-8 is amplied through the mitochondrial release of cytochrome c. J. Biol. Chem. 273:1658994 Lassmann H, Bancher C, Breitschopf H, Wegiel J, Bobinski M, et al. 1995. Cell death in Alzheimers disease evaluated by DNA fragmentation in situ. Acta Neuropathol. 89:3541 Li H, Zhu H, Xu CJ, Yuan J. 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491501 Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, et al. 1997. Cytochrome c and dATP-dependent formation of Apaf-1/ caspase-9 complex initiates an apoptotic protease cascade. Cell 91:47989 Linden R. 1994. The survival of developing neurons: a review of afferent control. Neuroscience 58:67182 Lindsay RM. 1979. Adult rat brain astrocytes support survival of both NGF-dependent and NGF-insensitive neurones. Nature 282:8082 Liu X, Kim CN, Yang J, Jemmerson R, Wang X. 1996. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:14757 Liu X, Li P, Widlak P, Zou H, Luo X, et al. 1998. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during

85

apoptosis. Proc. Natl. Acad. Sci. USA 95:846166 Liu X, Zou H, Slaughter C, Wang X. 1997. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89: 17584 Liu X, Zou H, Widlak P, Garrad W, Wang X. 1999. Activation of the apoptotic endonuclease DFF40 (CAD/CPAN): oligomerization and direct interaction with histone H1. J. Biol. Chem. 274:1383640 Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. 1998. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481 90 Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, et al. 1994. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:101730 Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. 1996. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimers disease. J. Neurosci. 16:5795811 Merry DE, Veis DJ, Hickey WF, Korsmeyer SJ. 1994. bcl-2 protein expression is widespread in the developing nervous system and retained in the adult Pns. Development 120:30111 Michaelidis TM, Sendtner M, Cooper JD, Airaksinen MS, Holtmann B, et al. 1996. Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 17:7589 Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, et al. 1995. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-decient mice. Science 267:150610 Muzio M, Chinnaiyan AM, Kischkel FC, ORourke K, Shevchenko A, et al. 1996.

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

86

NIJHAWAN

HONARPOUR

WANG Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW. 1995. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 92:68993 Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, et al. 1993. Mutations in Cu/ Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:5962; Erratum. 1993. Nature 364:362 Rosse T, Olivier R, Monney L, Rager M, Conus S, et al. 1998. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391:49699 Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, Yuan J. 1999. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22:62333 Saudou F, Finkbeiner S, Devys D, Greenberg ME. 1998. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:5566 Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, et al. 1997. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90:54958 Sells SF, Han SS, Muthukkumar S, Maddiwar N, Johnstone R, et al. 1997. Expression and function of the leucine zipper protein Par-4 in apoptosis. Mol. Cell. Biol. 17:382332 Sells SF, Wood DP Jr, Joshi-Barve SS, Muthukumar S, Jacob RJ, et al. 1994. Commonality of the gene programs induced by effectors of apoptosis in androgen-dependent and -independent prostate cells. Cell Growth Differ. 5:45766 Shibata N, Hirano A, Kobayashi M, Siddique T, Deng HX, et al. 1996. Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J. Neuropathol. Exp. Neurol. 55:48190

FLICE, a novel FADD-homologous ICE/ CED-3-like protease, is recruited to the CD95 (Fas/APO-1) deathinducing signaling complex. Cell 85:81727 Nagata S. 1997. Apoptosis by death factor. Cell 88:35565 Nasir J, Floresco SB, OKusky JR, Diewert VM, Richman JM, et al. 1995. Targeted disruption of the Huntingtons disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81:81123 Neame SJ, Rubin LL, Philpott KL. 1998. Blocking cytochrome c activity within intact neurons inhibits apoptosis. J. Cell Biol. 142:158393 Nordeen EJ, Nordeen KW, Sengelaub DR, Arnold AP. 1985. Androgens prevent normally occurring cell death in a sexually dimorphic spinal nucleus. Science 229: 67173 Okado N, Oppenheim RW. 1984. Cell death of motoneurons in the chick embryo spinal cord. IX. The loss of motoneurons following removal of afferent inputs. J. Neurosci. 4:163952 Oppenheim RW. 1981. Cell death of motoneurons in the chick embryo spinal cord. V. Evidence on the role of cell death and neuromuscular function in the formation of specic peripheral connections. J. Neurosci. 1:14151 Price DL, Sisodia SS. 1998. Mutant genes in familial Alzheimers disease and transgenic models. Annu. Rev. Neurosci. 21:479505 Puthalakath H, Huang DC, OReilly LA, King SM, Strasser A. 1999. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3:28796 Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, et al. 1998. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat. Genet. 20:198 202 Reed JC. 1997. Cytochrome c: Cant live with itcant live without it. Cell 91:55962

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

NEURAL APOPTOSIS Smale G, Nichols NR, Brady DR, Finch CE, Horton WE Jr. 1995. Evidence for apoptotic cell death in Alzheimers disease. Exp. Neurol. 133:22530 Srinivasula SM, Ahmad M, FernandesAlnemri T, Litwack G, Alnemri ES. 1996. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc. Natl. Acad. Sci. USA 93:1448691 Thornberry NA, Lazebnik Y. 1998. Caspases: enemies within. Science 281:131216 Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB. 1999. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ ADP exchange. Mol. Cell 3:15967 Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB. 1997. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:62737 Vekrellis K, McCarthy MJ, Watson A, Whiteld J, Rubin LL, Ham J. 1997. Bax promotes neuronal cell death and is downregulated during the development of the nervous system. Development 124:123949 Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, et al. 1999. Ca2 -induced apoptosis through calcineurin dephosphorylation of BAD. Science 284:33943 Wolozin B, Iwasaki K, Vito P, Ganjei JK, Lacana E, et al. 1996. Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 274:171013 Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ. 1997. Movement of Bax from the cytosol to mitochondria during apoptosis. J. Cell Biol. 139:128192 Wyllie AH. 1980. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:55556

87

Yamatsuji T, Matsui T, Okamoto T, Komatsuzaki K, Takeda S, et al. 1996a. G proteinmediated neuronal DNA fragmentation induced by familial Alzheimers diseaseassociated mutants of APP. Science 272:134952 Yamatsuji T, Okamoto T, Takeda S, Murayama Y, Tanaka N, Nishimoto I. 1996b. Expression of V642 APP mutant causes cellular apoptosis as Alzheimer trait-linked phenotype. EMBO J. 15:498509 Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, et al. 1997. Prevention of apoptosis by Bcl2: release of cytochrome c from mitochondria blocked. Science 275:112932 Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, et al. 1998. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94:73950 Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A. 1995. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntingtons disease gene homologue. Nat. Genet. 11:15563 Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. 1996. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 143-3 not BCL-X(L). Cell 87:61928 Zhang J, Liu X, Scherer DC, van Kaer L, Wang X, Xu M. 1998. Resistance to DNA fragmentation and chromatin condensation in mice lacking the DNA fragmentation factor 45. Proc. Natl. Acad. Sci. USA 95:12480 85 Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. 1997. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome cdependent activation of caspase-3. Cell 90:40513 Zou H, Li Y, Liu X, Wang X. 1999. An APAF1 cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 274(17):11549

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

NIJHAWAN

HONARPOUR

WANG C-1

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

Figure 1 Caspases are activated through two different pathways: Fas/FADD/Caspase-8 and Cytochrome c/Apaf-1/Caspase-9. Cytochrome c release from the mitochondria to the cytosol is regulated by Bcl-2 family members.

C-2 NIJHAWAN

HONARPOUR

WANG

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

Figure 2 Brain morphology of wild-type, Apaf-1, caspase-9, and caspase3 mutant mice demonstrating forebrain extrusions. Cytochrome c/Apaf1/Caspase-9 pathway is important for executing apoptosis during neural development. Courtesy of Razqallah Hakem and Tak Mak.

Annual Review of Neuroscience Volume 23, 2000

CONTENTS
Cortical and Subcortical Contributions to Activity-Dependent Plasticity in Primate Somatosensory Cortex, Edward G. Jones Microtubule-Based Transport Systems in Neurons: The Roles of Kinesins and Dyneins, Lawrence S. B. Goldstein, Zhaohuai Yang Apoptosis in Neural Development and Disease, Deepak Nijhawan, Narimon Honarpour, Xiaodong Wang Gain of Function Mutants: Ion Channels and G Protein-Coupled Receptors, Henry A. Lester, Andreas Karschin The Koniocellular Pathway in Primate Vision, Stewart H. C. Hendry, R. Clay Reid Emotion Circuits in the Brain, Joseph E. LeDoux Dopaminergic Modulation of Neuronal Excitability in the Striatum and Nucleus Accumbens, Saleem M. Nicola, D. James Surmeier, Robert C. Malenka Glutamine Repeats and Neurodegeneration, Huda Y. Zoghbi, Harry T. Orr Confronting Complexity: Strategies for Understanding the Microcircuitry of the Retina, Richard H. Masland , Elio Raviola Adaptation in Hair Cells, Ruth Anne Eatock Mechanisms of Visual Attention in the Human Cortex, Sabine Kastner and Leslie G. Ungerleider The Emergence of Modern Neuroscience: Some Implications for Neurology and Psychiatry, W. Maxwell Cowan, Donald H. Harter, Eric R. Kandel Plasticity and Primary Motor Cortex, Jerome N. Sanes, John P. Donoghue Guanylyl Cyclases as a Family of Putative Odorant Receptors, Angelia D. Gibson, David L. Garbers Neural Mechanisms of Orientation Selectivity in the Visual Cortex, David Ferster, Kenneth D. Miller Neuronal Coding of Prediction Errors, Wolfram Schultz, Anthony Dickinson Modular Organization of Frequency Integration in Primary Auditory Cortex, Christoph E. Schreiner, Heather L. Read, Mitchell L. Sutter Control of Cell Divisions in the Nervous System: Symmetry and Asymmetry, Bingwei Lu, Lily Jan, Yuh-Nung Jan Consciousness, John R. Searle The Relationship between Neuronal Survival and Regeneration, Jeffrey L. Goldberg, Ben A. Barres Neural Representation and the Cortical Code, R. Christopher deCharms, Anthony Zador Synaptic Plasticity and Memory: An Evaluation of the Hypothesis, S. J. Martin, P. D. Grimwood, R. G. M. Morris Molecular Genetics of Circadian Rhythms in Mammals, David P. King, Joseph S. Takahashi Parallel Pathways for Spectral Coding in Primate Retina, Dennis M. Dacey Pain Genes?: Natural Variation and Transgenic Mutants, Jeffrey S. Mogil, Lei Yu, Allan I. Basbaum 1 39 73 89 127 155

Annu. Rev. Neurosci. 2000.23:73-87. Downloaded from arjournals.annualreviews.org by Hong Kong University of Science & Technology on 07/02/09. For personal use only.

185 217 249 285 315

343 393 417 441 473 501 531 557 579 613 649 713 743 777