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Annu. Rev. Neurosci. 2000. 23:73–87 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 first described in two important studies. Genetic studies in Caenorhabditis elegans revealed three genes, ced3, ced4, and ced9, that specifically function in a pathway that controls developmental specific cell death (Ellis et al 1991). Second, Bcl-2, a human oncogene overexpressed in follicular lymphoma, was found to influence 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-specific cysteine proteases termed caspases that cleave their substrates with signature specificity after aspartic acid residues (Figure 1; see color insert) (Thornberry & Lazebnik 1998). Chromatin condensation, DNA
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In apoptotic cells. an apoptotic hallmark indicative of chromatin condensation (Liu et al 1998). BIOCHEMICAL MECHANISMS OF APOPTOSIS DNA Fragmentation and Chromatin Condensation During Apoptosis Annu. nuclear membrane breakdown. DFF40 has lower expression and no DNase activity. HMGs and histone H1 may target DFF40 to the internucleosomal linker region. After treatment with active DFF40. (b) the role of pro. chromatin-associated proteins such as high mobility group (HMG)-1. 1998. Rev. For personal use only. DNA fragmentation is mediated by a heterodimeric factor of 40 and 45 kDa. resulting in the exquisite pattern of internucleosomal DNA fragmentation commonly detected during apoptosis. and (c) evidence implicating apoptosis in neurodegenerative disease. Unlike other DNases.org by Hong Kong University of Science & Technology on 07/02/09. Cleaved DFF45 dissociates from DFF40. and it is commonly used as a biochemical marker for apoptosis (Wyllie 1980). DFF45. nuclei stained with a DNA dye exhibit bright particles. and the formation of apoptotic bodies are direct consequences of caspase activity.74 NIJHAWAN HONARPOUR WANG fragmentation into nucleosomal fragments. -2. Downloaded from arjournals. which suggests that DFF45 functions as a specific molecular chaperone important for DFF40 activation and synthesis (Liu et al 1998). The fragmentation of DNA into nucleosomal fragments was one of the first identified cellular features of apoptosis. 1999).23:73-87. In this review article. which has two caspase cleavage sites.annualreviews. Neurosci. In vivo. DFF activity can only be reconstituted by coexpressing the two subunits together (Liu et al 1998. 2000. is cleaved into three smaller fragments. Enari et al 1998). The review is divided into three sections: (a) a current description of caspase activation and DNA fragmentation in the apoptotic pathway. Enari et al 1998). inducing oligomerization of DFF40 into a large protein complex that has DNase activty (Liu et al 1999). DFF40 is significantly stimulated by internucleosomal. 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). and -14 and histone H1 but not core histones (Liu et al 1998. respectively.and anti-apoptotic proteins in neural development. 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. The multimeric nature of the active DFF40 may also contribute to apoptotic chromatin condensation by pulling cleaved nucleosomal fragments together. Thymocytes and . we focus on current understanding of biochemical pathways upstream and downstream of caspase activation in mammalian neuronal development and human neurological diseases. DFF40/CAD and DFF45/ICAD are encoded by novel genes and do not share sequence homology with other proteins with known functions. When expressed alone.

such as caspase-3. Apaf-1 forms a multimeric complex with cytochrome c (Li et al 1997. indicating that DNA fragmentation and chromatin condensation during apoptosis is not essential for normal development of a mouse (Zhang et al 1998). Activated caspase-9 released from the complex activates downstream caspases such as caspase-3. Apaf-1 is a 130-kDa cytosolic monomer consisting of three distinctive domains: a caspase recruitment domain. Downloaded from arjournals. and caspase-7. and a series of WD40 repeats (Zou et al 1997). On induction of apoptosis. caspases exist as inactive zymogens that. including anti-apoptotic members . where it undergoes autocatalytic activation (Boldin et al 1995. Fas ligand and TNF. Cytochrome c release not only initiates caspase activation by activating Apaf-1.org by Hong Kong University of Science & Technology on 07/02/09.23:73-87. During apoptosis. 1996. constituting the main caspase activity of apoptotic cells (Boldin et al 1996. Activated receptors recruit adaptor molecules such as FADD/MORT1 (Fas-associating protein with death domain). 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). ICAD null mice develop normally and are fertile. are activated by proteolytic cleavage (Thornberry & Lazebnik 1998). leading to the activation of caspase-8 intracellularly (Ashkenazi & Dixit 1998). Cytochrome c is a 13-kDa soluble electron transfer protein exclusively located in the mitochondrial intermembrane space. Chinnaiyan et al 1995. however. and caspase-7. Muzio et al 1996.NEURAL APOPTOSIS 75 splenocytes from mice deficient in ICAD die by apoptosis but fail to condense chromatin or fragment DNA (Zhang et al 1998). and a tumor necrosis factor (TNF) receptor at the cell surface. caspase-6. There are two relatively well-studied pathways that lead to caspase activation (Figure 1). bind and activate their receptors by inducing receptor trimerization (Nagata 1997). Zou et al 1999). which binds to Apaf-1. CED4 homologous domain. 2000. Caspase Activation Pathways In living cells. Srinivasula et al 1996). The release of cytochrome c is regulated by the Bcl-2 family of proteins. Activated caspase-8 will cleave and activate other downstream caspases. Srinivasula et al 1996). 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. caspase-6. One pathway involves death receptors. Neurosci. Muzio et al 1996. which recruit procaspase-8 to the receptor complex. Another means of caspase activation is through the release of cytochrome c from the mitochondria. the outer membrane of mitochondria becomes permeable to cytochrome c (Liu et al 1996). Annu. which usually exist as trimers. Apaf-1/ cytochrome c complexes are sufficient to recruit and activate procaspase-9. For personal use only. such as Fas. Rev. like DFF.annualreviews.

removal of unnecessary neurons. glial. amplifying the caspase activation signal (Li et al 1998. and Bax (Adams & Cory 1998). a pro-apoptotic Bcl-2 family member. Kluck et al 1997. binds to LC8. Activated caspase-8 cleaves and activates Bid. Extracellular survival signals inhibit apoptosis by activating the phosphotidylinositol3 kinase/Akt pathway. One possibility is that changes in mitochondrial membrane permeability induce mitochondrial swelling. Bax. Yang et al 1997).23:73-87. For personal use only. 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. Ca2 may induce apoptosis by activating the calcineurin-dependent phosphatase that dephosphorylates Bad (Wang et al 1999). In normal living cells. Bcl-2 and Bcl-xL and pro-apoptotic Bak. Conversely. In contrast. Neurosci. causing outer membrane rupture (Kroemer et al 1997. Rev. Phosphorylated Bad binds 14–3-3 protein and is sequestered in the cytoplasm. The mechanism of cytochrome c release and its regulation by the Bcl-2 family of proteins is not known.76 NIJHAWAN HONARPOUR WANG Annu. Li et al 1998. Other intrinsic death signals may regulate Bim translocation. Bad. Downloaded from arjournals. Bim. 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. Vander Heiden et al 1997. which suggests that neurons are . a cytoskeletal component. Burek & Oppenheim 1999). Overexpression of anti-apoptotic Bcl-2. Luo et al 1998. Apoptotic signals may activate the translocation of these factors to the mitochondria. and pattern formation (Burek & Oppenheim 1999). After cells are induced to die by apoptosis. Bax has also been shown to translocate from the cytoplasm to the mitochondria during apoptosis (Wolter et al 1997). 2000. Luo et al 1998). APOPTOSIS IN NEURAL DEVELOPMENT Apoptosis occurs throughout the nervous system in neuron.annualreviews. and neural progenitor cells. and Bid have been shown to directly cause cytochrome c release both in vivo and in vitro (Jurgensmeier et al 1998. or its close homologue Bcl-xL. increases in outer membrane permeability may occur independent of swelling. Rosse et al 1998). inducing caspase activation. A neuron’s chance for survival during development is believed to directly depend on the extent of its connections to a postsynaptic target. blocks cytochrome c release induced by a variety of apoptotic stimuli (Kim et al 1997. Bim. On the other hand. leading to Bad phosphorylation. the Bim/LC8 complex dissociates from the cytoskeleton and translocates to the mitochondria (Puthalakath et al 1999). which translocates to the mitochondria and induces cytochrome c release. whereas dephosphorylated Bad translocates to the mitochondria (Zha et al 1996). which then trigger cytochrome c release. 1999). The potential role of apoptosis during neural development includes optimization of synaptic connections. Kuwana et al 1998. Extracellular death signals such as Fas ligand or TNF activate caspase-8 intracellularly.org by Hong Kong University of Science & Technology on 07/02/09. Bak.

86% of the facial motor neurons in neonatal Bax-deficient mice survive (Deckwerth et al 1996).NEURAL APOPTOSIS 77 initially overproduced and then compete for target-derived neurotrophic factors (Cowan et al 1984). indicative of a gene dosing effect (Deckwerth et al 1996). Linden 1994). however. Rev. superior cervical ganglion. Consistently. 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). Neame et al 1998). Dubois-Dauphin et al 1994. there is a delay in cytochrome c release when NGF is removed.and antiapoptotic Bcl-2 family members in favor of survival (Allsopp et al 1993. Michaelidis et al 1996). Deshmukh & Johnson 1998.and anti-apoptotic Bcl-2 family members is important for neural survival during development. Farlie et al 1995). In Bax-deficient sympathetic neurons. 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. 2000. Nordeen et al 1985. and the retinal ganglion cell layer (Martinou et al 1994. Bax. ectopic expression of Bcl-2 in neurons results in brain hypertrophy. and dorsal root ganglia (Motoyama et al 1995). Notably. and apoptosis ensues (Deshmukh & Johnson 1998). spinal cord. the fifth lumbar dorsal root ganglion.annualreviews. Following NGF withdrawal from sympathetic neurons. however. in response to axotomy. For personal use only. overexpression of Bcl-2 reduces death probably by tilting the balance of pro. The balance between pro. but not Bcl-2. differentiating immature neurons of the brain. results in a 51% increase in facial motor neurons and yields 2.org by Hong Kong University of Science & Technology on 07/02/09. Deletion of Bax. 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.23:73-87. Postnatal Bcl-2 knockout mice have significant degeneration of the facial motor neurons. Motor neurons do not survive after axotomy in Bcl-2–deficient or wild-type mice. .5-fold more superior cervical ganglion neurons (Deckwerth et al 1996. which is predominantly expressed in the neonatal cortex. and facial motor nucleus. cytochrome c is released from the mitochondria to the cytosol. Neurosci. Alterations in Bcl-2 family members also regulate cell death following axotomy. Target- Annu. presynaptic cells. 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). which is widely expressed throughout the developing nervous system. with more neurons in the mesencephalic nucleus of the trigeminal nerve. dorsal root ganglion (L3) sensory neurons. and steroid hormones (Lindsay 1979. Okado & Oppenheim 1984. Mice deficient in Bcl-xL. Following axotomy. is important for mediating axotomy-induced apoptosis. Vekrellis et al 1997). Neurons also receive trophic support from glial cells. and sympathetic neurons in the superior cervical ganglion. the facial nucleus. implying that Bax catalyzes the release of cytochrome c on withdrawal of nerve growth factor (NGF) (Easton et al 1997. Farlie et al 1995. Downloaded from arjournals. die at embryonic day 13 (E13) with extensive apoptotsis in the postmitotic.

2000. Yoshida et al 1998). All these diseases have the following in common: (a) a familial form of the disease with a mendelian inheritance pattern. Downloaded from arjournals. and overexpression of the Ab peptide intracellularly in transgenic mice causes neurodegeneration. postmortem histopathology reveals either one or both of the following: (a) dystrophic neurites and intracellular neurofibrillary tangles. 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. (b) extracellular senile plaques composed of the 42. Alzheimer’s Disease Alzheimer disease (AD) is the most common cause of dementia among the elderly. which is a minor proteolytic product of APP. Cecconi et al 1998.78 NIJHAWAN HONARPOUR WANG derived trophic factors may promote survival by influencing Bax activity. see color insert). transgenic mice overexpressing FAD mutant APP (V717F).to 43-amino acid b-amyloid peptide (Ab). APOPTOSIS IN NEURODEGENERATIVE DISEASE If neurons die by apoptosis during development. Rev. These mice also possess craniofacial malformations and ventriclular obstruction by supernumerary mitotic and differentiating neurons (Cecconi et al 1998. caspase-9. For personal use only. Additionally. primarily early onset. presenilin-1 (PS1). knockout mice have prominent protrusions of the forebrain with exencephaly (Figure 2. Annu. and presenilin-2 (PS2) are associated with FAD (Price & Sisodia 1998). These studies further support in vitro data describing a linear cytochrome c–dependent caspase activation pathway: No activated caspase-3 is detected in the brains of Apaf-1 null mice (Cecconi et al 1998). Hakem et al 1998.org by Hong Kong University of Science & Technology on 07/02/09. (b) selective degeneration of particular neuronal subtypes. and (c) disease-associated cellular or extracellular aggregates. We focus on three well-studied disorders with strong implications of apoptosis in neurodegeneration: Alzheimer’s disease. Some forms of AD. Yoshida et al 1998). wild-type PS1. and basal forebrain cholinergic system. Despite their ubiquitous expression. Neurosci. are familial (FAD) and show an autosomal dominant inheritance pattern. and caspase-3 (Kuida et al 1996.annualreviews. The essential role of apoptosis in neural development is dramatically illustrated by mice deficient in Apaf-1. and amyotrophic lateral sclerosis. which are composed of the tau protein (Goedert et al 1996). In AD. amyloid precursor protein (APP). or both develop senile plaques composed . Huntington’s disease.23:73-87. Kuida et al 1998. In all three cases. Missense mutations in three genes. could the same pathways be activated in neurodegenerative disease? Recently. Ab is neurotoxic to primary neuronal cells. hippocampus. potentially preventing its translocation from the cytosol to the mitochondria. pathology resulting from the disruption of these genes mostly affects the developing brain and is lethal. AD is the result of damage to selective neuronal circuits in the neocortex.

1997). of Ab aggregates and dystrophic neurites similar to the histopathology seen in AD patients (Games et al 1995. slowing of voluntary movements. One important player might be Par-4. Group 1993). which suggests that the apoptogenic effects of mutant presenlin in culture are cell type specific. including the hippocampus.23:73-87.annualreviews. Neurosci. Smale et al 1995. or V642G) have increased DNA fragmentation and TUNEL staining. Mice deficient in huntingtin die between E8. Bancher et al 1996. Gervais et al 1999).b). Collab. Normal individuals have between 10 and 35 repeats whereas HD patients have from 37 to 121. Holcomb et al 1998). Lassmann et al 1995. or PS1 (A246E) overexpression sensitizes PC12 cells to apoptosis after b-amyloid treatment or trophic factor withdrawal (Deng et al 1996. 2000. which suggests an apoptotic death. and cognitive impairment (Harper 1991). i. using a herpes simplex virus. Degenerating neurons in APP V717F b-amyloid mice show chromatin segmentation and condensation and increased TUNEL staining. which was first identified in prostate cancer cells undergoing apoptosis (Sells et al 1994. wild-type PS2. Wolozin et al 1996). Downloaded from arjournals. which forms a polyglutamine expansion in a protein of approximately 350 kDa (Huntington’s Dis. Huntington’s Disease Huntington’s disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant pattern of inheritance characterized by hyperkinetic involuntary movements. In contrast. 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. FAD mutant PS2 (N141I). In a similar manner.org by Hong Kong University of Science & Technology on 07/02/09. DiFiglia et al 1997. Res. Bursztajn and colleagues (1998) found that overexpression of PS1 or PS1 (A246E) in primary mouse cortical culture does not enhance apoptosis. Rev. Huntingtin shares no significant 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. Par-4 is expressed at high levels in regions of the brain affected by AD. Scherzinger et al 1997. V642F. The major pathological change in HD patients is the selective degeneration of the cortex and striatum due to a CAG triplet expansion in the first exon of huntingtin.5 . Masliah et al 1996. 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. For personal use only.e. Little is known about which molecules mediate AD-associated apoptosis. inhibited by Bcl-2 coexpression (Yamatsuji et al 1996a. 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. Reddy et al 1998).NEURAL APOPTOSIS 79 Annu. 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).

and E10. thalamus. Sanchez et al (1999) show that FADD is recruited to and caspase-8 is activated on inclusions.5 (Duyao et al 1995. 2000. which suggests an anti-apoptotic role for huntingtin. including selective loss of . with an autosomal dominant pattern of inheritance (Brown 1995). and cerebral cortex whereas purkinje cells remained unaffected. Zeitlin et al 1995). These mice also have intranuclear neuronal inclusions that directly correlate with disease severity. hippocampus. which protects cells from oxidative damage induced by the superoxide anion (Deng et al 1993. which suggests that inclusions composed of polyglutamine repeats induce apoptosis by catalyzing caspase activation. 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). demonstrating selective neuronal loss. Rosen et al 1993).23:73-87. Transgenic mice overexpressing FALS mutant SOD1 exhibit a phenotype similar to FALS. Cell death was dependent on nuclear localization but was not associated with intranuclear inclusions. In fact. which suggests that activated caspase8 colocalizes with inclusions. For personal use only. However. Recently. Saudou et al (1998) demonstrate that mutant huntingtin selectively kills striatal but not purkinje neurons in culture by apoptosis.80 NIJHAWAN HONARPOUR WANG Annu. Furthermore. if neurons die apoptotically because of inclusion-induced caspase activation. Cell culture studies and in vivo studies of mouse models suggest that cell death induced by mutant huntingtin involves apoptosis. In huntingtin null mice.org by Hong Kong University of Science & Technology on 07/02/09. The role of inclusions in HD-related apoptosis is still unclear. neurodegenerative regions of the brain show increased TUNEL staining compared with age-matched wild-type controls. On the other hand. they identified activated caspase-8 in the insoluble protein fraction of postmortem HD brain. Finally.annualreviews. Some 10% of ALS cases are familial (FALS). embryonic ectodermal cells exhibit increased apoptosis. Rev. These authors induce apoptosis in primary cerebellar and striatal neurons by overexpressing a construct containing green fluorescent protein and an expanded CAG repeat. Downloaded from arjournals. Neuropathological analysis revealed prominent neuronal loss in the striata. they propose that the formation of inclusions might be a form of cellular defense because conditions that suppress inclusion formation result in increased apoptosis. 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. then drugs that inhibit inclusion formation or inhibit caspase activation would be of potential therapeutic benefit. Cotransfection with a dominant negative form of FADD inhibits apoptosis and reduces recruitment of caspase-8 to inclusions. debate has focused on the role of nuclear inclusions in neurodegeneration and HD pathogenesis. which is suggestive of apoptotic death. Neurosci. Nasir et al 1995. Some 20% of FALS cases are due to mutations in the ubiquitously expressed cytoplasmic Cu/Zn superoxide dismutase (SOD1).

caspase inhibitors would be less beneficial because cellular integrity would already be compromised by disease. Although these studies provide in vivo evidence that motor neurons in ALS mice die via apoptosis. upper and lower motor neurons. Moreover. and downstream. and chromatin condensation.23:73-87. In the former case. Dying PC12 cells or primary neurons exhibit characteristics of an apoptotic death. In SOD1 mutant mice. Bcl-2 overexpression in neurons of ALS mice significantly delays the onset but not the duration of disease (Kostic et al 1997). overexpression of dominant negative caspase-1 (DNcaspase-1) in neurons delays the duration but not the onset of disease (Friedlander et al 1997). mutant SOD1 may adopt a novel gain of function that is selectively toxic to motor neurons. Downloaded from arjournals. Bruijn et al 1997). Dal Canto & Gurney 1995. Ghadge et al (1997) showed that two different SOD1 mutations are selectively toxic to PC12 cells.NEURAL APOPTOSIS 81 Annu. For personal use only. . In contrast. which might explain the effect on disease course (Martinou et al 1994). Bcl-2 inhibits cytochrome c release. 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 presumably would also be activated. inclusions appear before disease onset and increase in abundance during the course of disease (Bruijn et al 1998). and hippocampal pyramidal mouse neurons but not astrocytes. Shibata et al 1996. Bruijn et al 1998). including shrunken cell bodies. increased TUNEL staining. FALS patients with SOD1 mutations and SOD1 mutant mice have neuronal and astrocytic cytoplasmic inclusions that are immunoreactive for SOD1 (Kato et al 1996. muscle atrophy. primary sympathetic. and paralysis (Gurney et al 1994. Although these studies provide hope that the apoptotic program is an effective therapeutic target. Rev. anti-apoptotic agents such as caspase inhibitors could be used to inhibit cell death and preserve cellular integrity. The toxic effects of mutant SOD1 have also been shown in culture. Using an adenoviral transducing system. and thus inhibiting release would delay onset. however. However. Neurosci. In FALS. PC12 cell death is inhibited by caspase inhibitors and Bcl-2 contransfection. CONCLUSION Much evidence has been gathered implicating apoptosis in neurodegenerative disease. important questions about how disease induces apoptosis remain: Is apoptosis the cell’s reaction to a permanent neuronal insult inflicted by disease or is the disease directly involved in activating the apoptotic program? In the latter case. Ripps et al 1995. These data may be explained by the differing effects of Bcl-2 and DNcaspase-1 on apoptosis. 2000. so caspase inhibition will only delay the course of disease.annualreviews. Cytochrome c release may be the trigger for the toxic effect of mutant SOD1. DNcaspase-1 inhibits caspase activity. upstream. 1999. once cytochrome c is released and caspases are activated.org by Hong Kong University of Science & Technology on 07/02/09. the cell is committed to die. and (b) DN-caspase-1 may not inhibit other caspases.

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Neurosci.NIJHAWAN s HONARPOUR s WANG C-1 Annu. . For personal use only. 2000. Cytochrome c release from the mitochondria to the cytosol is regulated by Bcl-2 family members.annualreviews.23:73-87. Figure 1 Caspases are activated through two different pathways: Fas/FADD/Caspase-8 and Cytochrome c/Apaf-1/Caspase-9. Rev.org by Hong Kong University of Science & Technology on 07/02/09. Downloaded from arjournals.

Courtesy of Razqallah Hakem and Tak Mak. . For personal use only. and caspase3 mutant mice demonstrating forebrain extrusions. Apaf-1.org by Hong Kong University of Science & Technology on 07/02/09.23:73-87. Figure 2 Brain morphology of wild-type. 2000. caspase-9.C-2 NIJHAWAN s HONARPOUR s WANG Annu. Neurosci. Rev. Cytochrome c/Apaf1/Caspase-9 pathway is important for executing apoptosis during neural development. Downloaded from arjournals.annualreviews.

Goldstein. James Surmeier. Zoghbi. David Ferster. Harter. Clay Reid Emotion Circuits in the Brain. Jeffrey S. B. John R. Zhaohuai Yang Apoptosis in Neural Development and Disease. Heather L. Mogil. Gibson.Annual Review of Neuroscience Volume 23. Ungerleider The Emergence of Modern Neuroscience: Some Implications for Neurology and Psychiatry. Angelia D. Ruth Anne Eatock Mechanisms of Visual Attention in the Human Cortex. 185 217 249 285 315 343 393 417 441 473 501 531 557 579 613 649 713 743 777 . Jerome N. D. Saleem M. Ben A. Lester. David P. Huda Y. Martin. Lawrence S. Stewart H. Jones Microtubule-Based Transport Systems in Neurons: The Roles of Kinesins and Dyneins. King. John P. Anthony Dickinson Modular Organization of Frequency Integration in Primary Auditory Cortex. David L. Downloaded from arjournals. M.org by Hong Kong University of Science & Technology on 07/02/09. Sabine Kastner and Leslie G. 2000 CONTENTS Cortical and Subcortical Contributions to Activity-Dependent Plasticity in Primate Somatosensory Cortex. Eric R. Yuh-Nung Jan Consciousness. Joseph E. R. Barres Neural Representation and the Cortical Code. Rev. LeDoux Dopaminergic Modulation of Neuronal Excitability in the Striatum and Nucleus Accumbens.23:73-87. Morris Molecular Genetics of Circadian Rhythms in Mammals. Robert C. Donald H. Sutter Control of Cell Divisions in the Nervous System: Symmetry and Asymmetry. Grimwood. Jeffrey L. Nicola. Christopher deCharms. Hendry. Allan I. Kenneth D. Kandel Plasticity and Primary Motor Cortex. Richard H. D. Christoph E. Mitchell L. Garbers Neural Mechanisms of Orientation Selectivity in the Visual Cortex. W. C. Bingwei Lu. R. Donoghue Guanylyl Cyclases as a Family of Putative Odorant Receptors. J. Dennis M. Lei Yu. Lily Jan. Dacey Pain Genes?: Natural Variation and Transgenic Mutants. Narimon Honarpour. Searle The Relationship between Neuronal Survival and Regeneration. Masland . For personal use only. Miller Neuronal Coding of Prediction Errors. Edward G. Elio Raviola Adaptation in Hair Cells. Orr Confronting Complexity: Strategies for Understanding the Microcircuitry of the Retina. Takahashi Parallel Pathways for Spectral Coding in Primate Retina. P. Neurosci. Harry T. 2000. Henry A. Andreas Karschin The Koniocellular Pathway in Primate Vision. Sanes.annualreviews. Xiaodong Wang Gain of Function Mutants: Ion Channels and G Protein-Coupled Receptors. Maxwell Cowan. R. Malenka Glutamine Repeats and Neurodegeneration. Schreiner. Joseph S. Anthony Zador Synaptic Plasticity and Memory: An Evaluation of the Hypothesis. Basbaum 1 39 73 89 127 155 Annu. S. Read. Goldberg. Deepak Nijhawan. G. Wolfram Schultz.

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