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Annu. Rev. Neurosci. 2000. 23:73–87Copyright 2000 by Annual Reviews. All rights reserved
0147–006X/00/0301–0073$12.00 73
APOPTOSIS IN NEURAL DEVELOPMENT
AND DISEASE
Deepak Nijhawan, Narimon Honarpour, andXiaodong Wang
Howard Hughes Medical Institute and Department of Biochemistry, University of Texas
Southwestern Medical Center at Dallas, Dallas, Texas 75235; e-mail:
[email protected], [email protected],
Key Words caspase, Bcl-2, cytochrome c, Apaf-1, neurodegenerative
Abstract Cell death via apoptosis is a prominent feature in mammalian neuraldevelopment. Recent studies into the basic mechanism of apoptosis have revealedbiochemical pathways that control and execute apoptosis in mammalian cells. Proteinfactors in these pathways play important roles during development in regulating the
balance between neuronal life and death. Additionally, mounting evidence indicatessuch 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 man-
ifestations 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 apop-totic pathway were first described in two important studies. Genetic studies in
Caenorhabditis elegans revealed three genes, ced3, ced4, and ced9, that specifi-
cally function in a pathway that controls developmental specific cell death (Ellis
et al 1991). Second, Bcl-2, a human oncogene overexpressed in follicular lym-
phoma, 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 acti-
vate 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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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 path-
ways 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 CondensationDuring Apoptosis
The fragmentation of DNA into nucleosomal fragments was one of the first iden-
tified 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: FreeDNA ends are end labeled with biotinylated poly-dUTP by terminal deoxytrans-
ferase 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, whichsuggests that DFF45 functions as a specific molecular chaperone important for
DFF40 activation and synthesis (Liu et al 1998). Unlike other DNases, DFF40 is
significantly 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 internu-
cleosomal 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
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NEURAL APOPTOSIS 75
splenocytes from mice deficient in ICAD die by apoptosis but fail to condense
chromatin or fragment DNA (Zhang et al 1998). ICAD null mice develop nor-
mally and are fertile, indicating that DNA fragmentation and chromatin conden-
sation during apoptosis is not essential for normal development of a mouse (Zhang
et al 1998).
Caspase Activation PathwaysIn 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). Acti-
vated receptors recruit adaptor molecules such as FADD/MORT1 (Fas-associat-
ing 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 cas-
pase-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 sufficient to recruit and activate procaspase-9. Acti-
vated caspase-9 released from the complex activates downstream caspases suchas caspase-3, caspase-6, and caspase-7.
Regulation of Cytochrome c Release by the Bcl-2 Familyof 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
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76 NIJHAWAN HONARPOUR WANG
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 mito-
chondrial 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). Extra-
cellular survival signals inhibit apoptosis by activating the phosphotidylinositol-
3 kinase/Akt pathway, leading to Bad phosphorylation. Phosphorylated Bad binds14–3-3 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 reg-
ulate 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 trans-
locates 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 pro-
genitor 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 unnec-
essary neurons, and pattern formation (Burek & Oppenheim 1999). A neuron’s
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
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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, pre-
synaptic 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 mito-
chondria to the cytosol, and apoptosis ensues (Deshmukh & Johnson 1998). In
Bax-deficient sympathetic neurons, however, there is a delay in cytochrome c
release when NGF is removed, implying that Bax catalyzes the release of cyto-
chrome c on withdrawal of nerve growth factor (NGF) (Easton et al 1997, Desh-
mukh & Johnson 1998, Neame et al 1998).
The balance between pro- and anti-apoptotic Bcl-2 family members is impor-
tant for neural survival during development. Mice deficient 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 imma-
ture 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 significant 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 fifth
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 axo-
tomy. Bax, but not Bcl-2, is important for mediating axotomy-induced apoptosis.
Motor neurons do not survive after axotomy in Bcl-2–deficient or wild-type mice;
however, in response to axotomy, 86% of the facial motor neurons in neonatal
Bax-deficient mice survive (Deckwerth et al 1996). Following axotomy, over-
expression of Bcl-2 reduces death probably by tilting the balance of pro- and anti-
apoptotic 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-
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78 NIJHAWAN HONARPOUR WANG
derived trophic factors may promote survival by influencing Bax activity, poten-
tially preventing its translocation from the cytosol to the mitochondria.
The essential role of apoptosis in neural development is dramatically illustrated
by mice deficient 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 c–dependent caspase activation pathway: No activated cas-
pase-3 is detected in the brains of Apaf-1 null mice (Cecconi et al 1998).
APOPTOSIS IN NEURODEGENERATIVE DISEASE
If neurons die by apoptosis during development, could the same pathways be
activated in neurodegenerative disease? Recently, investigation into neurodegen-
erative disease has focused on this question in the hope that apoptosis may ulti-mately 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: Alzheimer’s disease, Huntington’s 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) selec-
tive degeneration of particular neuronal subtypes, and (c) disease-associated cel-
lular or extracellular aggregates.
Alzheimer’s 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, pri-marily early onset, are familial (FAD) and show an autosomal dominant inheri-
tance 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 neurofibrillary 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
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NEURAL APOPTOSIS 79
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). Degen-
erating 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 sen-
sitizes PC12 cells to apoptosis after b-amyloid treatment or trophic factor with-
drawal (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
specific. The importance of apoptosis in AD pathogenesis is supported by evi-
dence describing increased TUNEL staining and activated caspases in postmor-
tem 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. Oneimportant player might be Par-4, which was first identified 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-regula-
tion because neurons transfected with Par-4 antisense message survive treatment
(Guo et al 1998).
Huntington’s Disease
Huntington’s disease (HD) is a fatal neurodegenerative disorder with an autoso-
mal 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 degenerationof the cortex and striatum due to a CAG triplet expansion in the first exon of
huntingtin, which forms a polyglutamine expansion in a protein of approximately
350 kDa (Huntington’s Dis. Collab. Res. Group 1993). Normal individuals have
between 10 and 35 repeats whereas HD patients have from 37 to 121. Immuno-
histological analysis of brains from HD patients and the HD mouse model
revealed neuronal nuclear inclusions throughout the brain that are immunoreac-
tive 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 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. Mice deficient in huntingtin die between E8.5
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80 NIJHAWAN HONARPOUR WANG
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 hun-
tingtin cDNA with 48 or 89 but not 16 CAG repeats exhibits a progressive neu-
rological 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 neurodegen-
eration and HD pathogenesis. Saudou et al (1998) demonstrate that mutant hun-
tingtin 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, whichsuggests that inclusions composed of polyglutamine repeats induce apoptosis by
catalyzing caspase activation. These authors induce apoptosis in primary cere-
bellar and striatal neurons by overexpressing a construct containing green fluo-
rescent 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 identified activated caspase-8 in the insoluble
protein fraction of postmortem HD brain, which suggests that activated caspase-
8 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 benefit.
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 dom-
inant 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
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NEURAL APOPTOSIS 81
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 cyto-
plasmic 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 significantly 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 overexpressingBcl-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 apop-
tosis 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, 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 beneficial because cellular integrity
would already be compromised by disease.
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82 NIJHAWAN HONARPOUR WANG
All three of the diseases reviewed are associated with intracelluar or extracel-
lular protein aggregation (Kakizuka 1998). Recent reports suggest that neurode-
generation may be the result of protein aggregation that directly activates caspases
and induces apoptosis. It is difficult 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 apopto-
genic proteins to protein aggregates may activate apoptotic pathways because
oligomerization steps are required for the formation of active multimeric com-
plexes 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
We thank Drs. Razqallah Hakem and Tak Mak for pictures of wild-type, Apaf-
1, 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.
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NIJHAWAN s HONARPOUR s WANG C-1
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.
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Figure 2 Brain morphology of wild-type, Apaf-1, caspase-9, and caspase-
3 mutant mice demonstrating forebrain extrusions. Cytochrome c /Apaf-
1/Caspase-9 pathway is important for executing apoptosis during neural
development. Courtesy of Razqallah Hakem and Tak Mak.
C-2 NIJHAWAN s HONARPOUR s WANG
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Annual Review of Neuroscience
Volume 23, 2000
CONTENTS
Cortical and Subcortical Contributions to Activity-Dependent Plasticity in
Primate Somatosensory Cortex, Edward G. Jones 1
Microtubule-Based Transport Systems in Neurons: The Roles of Kinesinsand Dyneins, Lawrence S. B. Goldstein, Zhaohuai Yang 39
Apoptosis in Neural Development and Disease, Deepak Nijhawan,
Narimon Honarpour, Xiaodong Wang 73
Gain of Function Mutants: Ion Channels and G Protein-Coupled
Receptors, Henry A. Lester, Andreas Karschin 89
The Koniocellular Pathway in Primate Vision, Stewart H. C. Hendry, R.
Clay Reid 127
Emotion Circuits in the Brain, Joseph E. LeDoux 155
Dopaminergic Modulation of Neuronal Excitability in the Striatum and
Nucleus Accumbens, Saleem M. Nicola, D. James Surmeier, Robert C.
Malenka 185
Glutamine Repeats and Neurodegeneration, Huda Y. Zoghbi, Harry T.
Orr 217
Confronting Complexity: Strategies for Understanding the Microcircuitry
of the Retina, Richard H. Masland , Elio Raviola 249
Adaptation in Hair Cells, Ruth Anne Eatock 285
Mechanisms of Visual Attention in the Human Cortex, Sabine Kastner
and Leslie G. Ungerleider 315
The Emergence of Modern Neuroscience: Some Implications for
Neurology and Psychiatry, W. Maxwell Cowan, Donald H. Harter, Eric
R. Kandel 343
Plasticity and Primary Motor Cortex, Jerome N. Sanes, John P.
Donoghue 393
Guanylyl Cyclases as a Family of Putative Odorant Receptors, Angelia D.
Gibson, David L. Garbers 417Neural Mechanisms of Orientation Selectivity in the Visual Cortex, David
Ferster, Kenneth D. Miller 441
Neuronal Coding of Prediction Errors, Wolfram Schultz, Anthony
Dickinson 473
Modular Organization of Frequency Integration in Primary Auditory
Cortex, Christoph E. Schreiner, Heather L. Read, Mitchell L. Sutter 501
Control of Cell Divisions in the Nervous System: Symmetry and
Asymmetry, Bingwei Lu, Lily Jan, Yuh-Nung Jan 531
Consciousness, John R. Searle 557
The Relationship between Neuronal Survival and Regeneration, Jeffrey L.
Goldberg, Ben A. Barres 579
Neural Representation and the Cortical Code, R. Christopher deCharms, Anthony Zador 613
Synaptic Plasticity and Memory: An Evaluation of the Hypothesis, S. J.
Martin, P. D. Grimwood, R. G. M. Morris 649
Molecular Genetics of Circadian Rhythms in Mammals, David P. King,
Joseph S. Takahashi 713
Parallel Pathways for Spectral Coding in Primate Retina, Dennis M.
Dacey 743
Pain Genes?: Natural Variation and Transgenic Mutants, Jeffrey S. Mogil,
Lei Yu, Allan I. Basbaum 777