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Figure 1.
Ischemic necrotic vs apoptotic death. Postischemic cell death may be necrotic or apoptotic, depending in part on the severity of hypoxia. Necrotic cell death pathways are for the most part irreversible. On the other hand, caspase pathways are activated in territories subjected to moderate hypoxia leading to apoptotic cell death over a more prolonged period. Apoptosis may be aborted by timely reperfusion or by caspase inhibition.

Ischemic necrotic vs apoptotic death. Postischemic cell death may be necrotic or apoptotic, depending in part on the severity of hypoxia. Necrotic cell death pathways are for the most part irreversible. On the other hand, caspase pathways are activated in territories subjected to moderate hypoxia leading to apoptotic cell death over a more prolonged period. Apoptosis may be aborted by timely reperfusion or by caspase inhibition.

Figure 2.
Cellular pathogenesis in Huntington disease. Expression of mutant huntingtin (m-htt) generates a toxic reaction within a specific population of cells. The cause for the vulnerability of certain cell types is not understood. As a certain level of "cell toxicity" is reached, and caspase 1 is activated, caspase 1 may directly or indirectly activate caspase 3, and both of these caspases then cleave the full-length htt molecule generating the toxic fragments (m-htt fragment). As a detrimental feedback loop m-htt fragments exacerbate cell toxicity and accelerate the formation of neuronal intranuclear inclusions (NIIs) causing further caspase activation. Progression of cell dysfunction (in part manifested as a decreased number of specific neuroreceptors) and cell death translate at the organismal level to symptomatic disease progression.

Cellular pathogenesis in Huntington disease. Expression of mutant huntingtin (m-htt) generates a toxic reaction within a specific population of cells. The cause for the vulnerability of certain cell types is not understood. As a certain level of "cell toxicity" is reached, and caspase 1 is activated, caspase 1 may directly or indirectly activate caspase 3, and both of these caspases then cleave the full-length htt molecule generating the toxic fragments (m-htt fragment). As a detrimental feedback loop m-htt fragments exacerbate cell toxicity and accelerate the formation of neuronal intranuclear inclusions (NIIs) causing further caspase activation. Progression of cell dysfunction (in part manifested as a decreased number of specific neuroreceptors) and cell death translate at the organismal level to symptomatic disease progression.

1.
Friedlander  RMGagliardini  VHara  H  et al.  Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med. 1997;185933- 940Article
2.
Friedlander  RMBrown  RHGagliardini  VWang  JYuan  J Inhibition of ICE slows ALS in mice [letter]. Nature. 1997;38831Article
3.
Yakovlev  AGKnoblach  SMFan  L  et al.  Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci. 1997;177415- 7424
4.
Hara  HFriedlander  RMGagliardini  V  et al.  Inhibition of interleukin 1 beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A. 1997;942007- 2012Article
5.
Fink  KBAndrews  LJButler  WE  et al.  Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase 1 cascade. Neuroscience. 1999;941213- 1218Article
6.
Ona  VOLi  MVonsattel  JP  et al.  Inhibition of caspase 1 slows disease progression in a mouse model of Huntington's disease. Nature. 1999;399263- 267Article
7.
Kostic  VJackson-Lewis  Vde Bilbao  F  et al.  Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science. 1997;277559- 562Article
8.
Friedlander  RMYuan  J ICE, neuronal apoptosis and neurodegeneration. Cell Death Differ. 1998;5823- 831Article
9.
Yuan  JYHorvitz  HR The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death. Dev Biol. 1990;13833- 41Article
10.
Yuan  JShaham  SLedoux  S  et al.  The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993;75641- 652Article
11.
Miura  MZhu  HRotello  R  et al.  Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 1993;75653- 660Article
12.
Friedlander  RMGagliardini  V  et al.  Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta- converting enzyme-mediated apoptosis. J Exp Med. 1996;184717- 724Article
13.
Li  PAllen  HBanerjee  S  et al.  Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell. 1995;80401- 411Article
14.
Enari  MSakahira  HYokoyama  H  et al.  A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998;39143- 50Article
15.
Pasinelli  PBorchelt  DRHouseweart  MK  et al.  Caspase 1 is activated in neural cells and tissue with amyotrophic lateral sclerosis–associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A. 1998;9515763- 15768Article
16.
Charriaut-Marlangue  CMargaill  IRepresa  A  et al.  Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab. 1996;16186- 194Article
17.
Endres  MNamura  SShimizu-Sasamata  M  et al.  Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab. 1998;18238- 247Article
18.
Du  CHu  RCsernansky  CA  et al.  Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab. 1996;16195- 201Article
19.
Schielke  GPYang  GYShivers  BDBetz  AL Reduced ischemic brain injury in interleukin-1 beta converting enzyme–deficient mice. J Cereb Blood Flow Metab. 1998;18180- 185Article
20.
Farber  AConnors  JPFriedlander  RM  et al.  A specific inhibitor of apoptosis decreases tissue injury after intestinal ischemia-reperfusion in mice. J Vasc Surg. 1999;30752- 760Article
21.
Ghadge  GDLee  JPBindokas  VP  et al.  Mutant superoxide dismutase-1–linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection. J Neurosci. 1997;178756- 8766
22.
Li  MOna  VOGuegan  C  et al.  Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 2000;288335- 339Article
23.
Wellington  CLEllerby  LMHackam  AS  et al.  Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem. 1998;2739158- 9167Article
24.
Thomas  LBGates  DJRichfield  EK  et al.  DNA end labeling (TUNEL) in Huntington's disease and other neuropathological conditions. Exp Neurol. 1995;133265- 272Article
25.
Reddy  PHWilliams  MCharles  V  et al.  Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet. 1998;20198- 202Article
26.
Hodgson  JGAgopyan  NGutekunst  CA  et al.  A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron. 1999;23181- 192Article
27.
DiFiglia  MSapp  EChase  KO  et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;2771990- 1993Article
Basic Science Seminars in Neurology
September 2000

Role of Caspase 1 in Neurologic Disease

Author Affiliations

From the Neuroapoptosis Laboratory, Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

 

HASSAN M.FATHALLAH-SHAYKHMD

Arch Neurol. 2000;57(9):1273-1276. doi:10.1001/archneur.57.9.1273

In recent years substantial advances have taken place in understanding the mechanistic pathways mediating neuronal cell death in a variety of neurologic diseases. Since the central nervous system (CNS) has little, if any, power of functional neuronal regeneration, prevention of neuronal cell death is an important target of modern neurotherapeutics. A detailed understanding of the mechanisms mediating neuronal cell death is required to effectively slow the progression of neurologic diseases featuring apoptosis. Increasing evidence demonstrates that blocking cell death pathways in cells otherwise fated to die (ie, following stroke, trauma, or in neurodegenerative diseases) improves neurologic outcome.17

Broadly, cells can die by 1 of 2 mechanisms: necrosis or apoptosis. Necrotic cell death is a more passive form of cell death, where the stimulus itself alters cell homeostasis resulting in its death. On the other hand, apoptosis (also known as programmed cell death) is a more active and physiologic form of cell death, where the death stimulus triggers the cellular suicide program, and it is this program (and not the stimulus itself) that mediates the demise of the cell.8

Pathways mediating apoptosis have been preserved through evolution. Specific mediators of apoptosis were first identified through elegant genetic studies of the nematode Caenorhabditis Elegans. Several genes required for cell death were identified in the worm (ced-3 and ced-4).9 The interleukin (IL) 1β converting enzyme (ICE) was the first mammalian gene identified with sequence homology to ced-3.10 Extensive studies have demonstrated that ICE is an important mediator of apoptosis in mammalian cells and a functional homolog of ced-3.11 Since the identification of ICE as a mediator of apoptosis, an additional 13 mammalian homologs have been identified. This family of cell death cysteine proteases has been called caspases. In recent years, caspases have been identified as central mediators of cell death in a variety of neurologic diseases. The role of caspases, in particular caspase 1, in neurologic diseases will be the focus of this review.

Following exposure to an apoptotic death–promoting stimulus, a tightly regulated cascade becomes activated executing the death of the cell. Caspase activation results in cell death by destroying molecules required for cell survival and activating others mediating the suicide program. Caspase 1 and caspase 3 are the 2 caspase family members for which most information has been generated. Caspase 1, the founding member of the caspase family, is responsible for cleavage of pro-IL-1β to the mature and active form of the cytokine.11 Evidence indicates that following caspase 1 activation, binding of mature IL-1β to its type 1 receptor plays an important role mediating neuronal cell death.12 Since caspase 1 is required in mice (and likely also in humans) to process pro-IL-1β, detection of mature IL-1β indicates activation of caspase 1.13 We have used detection of mature IL-1β as a sensitive and specific method to ascertain caspase 1 activation. Caspase 3, another important mediator of apoptosis, seems to be the end-pathway effector for most apoptotic pathways. Caspase 3 activates the DNase responsible for the cleavage of DNA into the classic DNA fragments detected on agarose gels and by TUNEL staining.14 Caspase 1 and caspase 3 activation have been demonstrated in a variety of neurologic diseases.16,15

Central nervous system degeneration may be broadly classified as acute or chronic. In acute neurologic diseases (ie, stroke and traumatic brain and spinal cord injury), the greatest magnitude of cell death occurs shortly following the insult (Figure 1). However, cell death is detected for up to 3 weeks following the initial insult. In chronic neurologic diseases (eg, amyotrophic lateral sclerosis [ALS], Huntington disease [HD], and Alzheimer disease), the presence of the apoptotic stimulus is constant, and therefore cell death occurs over a period of years. Interestingly, caspase-mediated pathways are shared as part of the pathogenic progression in acute and chronic neurodegeneration.

ACUTE CELL DEATH DISEASES

Of the acute CNS disorders featuring apoptotic cell death, cerebral ischemia is the most thoroughly studied and best understood. Other diseases in the acute cell death category include traumatic brain injury and spinal cord injury. I will use ischemia as the prototype disease in the acute category; however, similar pathways to play a role in the other acute cell death diseases as well. Following ischemia, both necrotic and apoptotic cell death are detected. Necrotic death occurs at the core of the infarct area where the insult is most severe. However, in the ischemic penumbra, where the ischemic insult is not as severe, apoptotic mechanisms are triggered and TUNEL-positive cells are clearly identified.16 The speed of detecting apoptotic bodies bears direct correlation to the magnitude of the ischemic insult. Following 2 hours of focal ischemia, apoptotic cells are detected within 6 hours.4 On the other hand, following 30 minutes of transient global ischemia, apoptotic cells are not detected for 24 hours and are detected up to 2 weeks following the insult.17,18 This extended time frame of apoptotic cell death occurs not only in ischemia but also in CNS trauma.18 These results provide very important evidence demonstrating that the activation of cell death pathways is not an all-or-none phenomenon, but rather a graded process where the magnitude of the activation of the apoptotic pathways is directly proportional to the magnitude of the effector death cascade. Initial activation of caspase pathways is not an irreversible process, and it does not always lead to cell death. Therefore, if intervention occurs early enough, cell death can be aborted, thus rescuing neuronal populations and improving neurologic outcome.

Following ischemic or traumatic injury, caspase 1 and caspase 3 are activated.35 Three main approaches have been used to evaluate whether caspase activation plays a functional role mediating cell death and neurologic deterioration. First, intracerebroventricular administration of synthetic caspase peptide inhibitors has been used as a pharmacologic approach to block caspase activation.1,4,19 Second, my colleagues and I1 have used a transgenic mouse expressing a dominant negative mutant of caspase 1 under the control of the neuron specific enolase promoter (NSE-M17Z).1,4,19 We demonstrated that this construct is a functional caspase 1–dominant negative inhibitor. This construct might also inhibit additional caspases. The third approach involves the use of caspase 1–deficient mice.1,4,19 Reduction of tissue damage and improved neurologic outcome occurs in rodents treated with caspase peptide inhibitors, in mice expressing the caspase 1–dominant negative inhibitor, and in caspase 1–deficient mice. These data provide strong evidence of an important functional role of the caspase family in mediating tissue injury and neurologic dysfunction following an ischemic insult.

These findings are not particular to ischemic brain damage; similar protection is afforded by caspase peptide inhibitors in a small-bowel ischemic paradigm20 and following traumatic brain injury.3,5 These results taken together demonstrate that caspase-mediated cell death is a shared common pathway playing an important functional role following CNS trauma and ischemia.

CHRONIC CELL DEATH DISEASES

Abundant evidence implicates caspase-driven apoptotic pathways in the pathogenesis of several chronic neurodegenerative diseases. This evidence has been generated by using a variety of complementary approaches, including evaluating human tissue and using transgenic mouse and neurotoxin models and in vitro models. I will discuss the evidence linking caspase activity with the pathogenesis of 2 neurodegenerative diseases: ALS and HD. Evidence linking caspase to additional neurodegenerative diseases also exists.

Amyotrophic Lateral Sclerosis

Apoptotic cell death has been detected in spinal cords of patients with ALS. In addition, clear evidence for caspase 1 activation and apoptotic cell death has been detected using in vitro models of ALS.15 Mutant SOD-1–mediated apoptotic cell death in vitro is effectively inhibited by synthetic peptide caspase inhibitors.21 These results provide evidence for the activation of caspases by the mutant SOD-1 gene. Further specific in vivo evidence for caspase 1 activation was found using a transgenic mouse model of familial ALS.15 Extended survival occurs in this ALS mouse model when the mouse is crossbred with a transgenic mouse expressing either the caspase 1–dominant negative inhibitor or Bcl-2.2,7 Also recently demonstrated has been a delay in disease progression and mortality in ALS mice treated with a caspase inhibitor.22

Huntington Disease

Huntington disease is 1 of 8 diseases where the etiologic mutation has been determined to be a CAG expansion encoding for an abnormal polyglutamine stretch in the gene identified as a cause for the disease. Abundant evidence links several of these diseases with aberrant caspase function. Interestingly, several of these disease gene products are themselves caspase substrates.23 The particular relation of caspase-mediated cleavage of these proteins with disease progression remains controversial. However, the resultant cleavage fragments seem to have a toxic gain of function, providing a direct link between the caspase family and polyglutamine diseases. Much information exists linking caspase apoptotic pathways with the progression of HD. Apoptotic cell death has been clearly demonstrated in the striatum of humans with HD as well as in transgenic mouse models.2426 In addition, caspase 1 activation occurs in brains of humans and mice with HD.6 Interestingly, huntingtin itself is cleaved by caspase 1 and caspase 3.23 Generation of these toxic fragments seems to be required for the pathogenic disease progression as well as for the formation of neuronal intranuclear inclusions (Figure 2), which are detected in brain specimens of both humans with HD and mouse models.27 Caspase inhibition by either the caspase 1–dominant negative transgene or synthetic peptide caspase inhibitors delays disease onset, slows progression, and extends survival in a transgenic mouse model of HD.6

CONCLUSIONS

Caspase 1 activation occurs in models of cerebral ischemia and trauma, ALS, and HD.46,15 It also occurs in human HD brain specimens.6 In addition, inhibition of caspase 1 function improves neurologic outcome in the above-mentioned diseases. Since caspase-mediated apoptotic pathways are shared between acute and chronic neurologic conditions, effective therapies for one might be effective for others. However, differences will clearly exist in designing effective therapies for the treatment of acute and chronic conditions. As our understanding of the specific mechanistic pathways mediating neurodegeneration increases, we approach being able to develop rational targeted pharmacotherapy for the treatment of diseases featuring caspase-driven apoptosis.

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Article Information

Accepted for publication March 13, 2000.

Dr Friedlander is supported by grants from the Muscular Dystrophy Association, Phoenix, Ariz, the Hereditary Disease Foundation, Los Angeles, Calif, and the Huntington's Disease Society of America, New York, NY, and by a Bayer and Upjohn grant from the Joint Section of Cerebrovascular Surgery, Chicago, Ill. He is also a member of the Cure Huntington's Disease Initiative of the Hereditary Disease Foundation, Los Angeles, and the Huntington's Disease Society of America Coalition for the Cure, New York, NY.

I thank Eugenia Friedlander, JD, for her editorial assistance.

Reprints: Robert M. Friedlander, MD, MA, Neuroapoptosis Laboratory, Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 (e-mail: rfriedlander@rics.bwh.harvard.edu).

References
1.
Friedlander  RMGagliardini  VHara  H  et al.  Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med. 1997;185933- 940Article
2.
Friedlander  RMBrown  RHGagliardini  VWang  JYuan  J Inhibition of ICE slows ALS in mice [letter]. Nature. 1997;38831Article
3.
Yakovlev  AGKnoblach  SMFan  L  et al.  Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci. 1997;177415- 7424
4.
Hara  HFriedlander  RMGagliardini  V  et al.  Inhibition of interleukin 1 beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A. 1997;942007- 2012Article
5.
Fink  KBAndrews  LJButler  WE  et al.  Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase 1 cascade. Neuroscience. 1999;941213- 1218Article
6.
Ona  VOLi  MVonsattel  JP  et al.  Inhibition of caspase 1 slows disease progression in a mouse model of Huntington's disease. Nature. 1999;399263- 267Article
7.
Kostic  VJackson-Lewis  Vde Bilbao  F  et al.  Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science. 1997;277559- 562Article
8.
Friedlander  RMYuan  J ICE, neuronal apoptosis and neurodegeneration. Cell Death Differ. 1998;5823- 831Article
9.
Yuan  JYHorvitz  HR The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death. Dev Biol. 1990;13833- 41Article
10.
Yuan  JShaham  SLedoux  S  et al.  The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993;75641- 652Article
11.
Miura  MZhu  HRotello  R  et al.  Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 1993;75653- 660Article
12.
Friedlander  RMGagliardini  V  et al.  Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta- converting enzyme-mediated apoptosis. J Exp Med. 1996;184717- 724Article
13.
Li  PAllen  HBanerjee  S  et al.  Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell. 1995;80401- 411Article
14.
Enari  MSakahira  HYokoyama  H  et al.  A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998;39143- 50Article
15.
Pasinelli  PBorchelt  DRHouseweart  MK  et al.  Caspase 1 is activated in neural cells and tissue with amyotrophic lateral sclerosis–associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A. 1998;9515763- 15768Article
16.
Charriaut-Marlangue  CMargaill  IRepresa  A  et al.  Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab. 1996;16186- 194Article
17.
Endres  MNamura  SShimizu-Sasamata  M  et al.  Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab. 1998;18238- 247Article
18.
Du  CHu  RCsernansky  CA  et al.  Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab. 1996;16195- 201Article
19.
Schielke  GPYang  GYShivers  BDBetz  AL Reduced ischemic brain injury in interleukin-1 beta converting enzyme–deficient mice. J Cereb Blood Flow Metab. 1998;18180- 185Article
20.
Farber  AConnors  JPFriedlander  RM  et al.  A specific inhibitor of apoptosis decreases tissue injury after intestinal ischemia-reperfusion in mice. J Vasc Surg. 1999;30752- 760Article
21.
Ghadge  GDLee  JPBindokas  VP  et al.  Mutant superoxide dismutase-1–linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection. J Neurosci. 1997;178756- 8766
22.
Li  MOna  VOGuegan  C  et al.  Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 2000;288335- 339Article
23.
Wellington  CLEllerby  LMHackam  AS  et al.  Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem. 1998;2739158- 9167Article
24.
Thomas  LBGates  DJRichfield  EK  et al.  DNA end labeling (TUNEL) in Huntington's disease and other neuropathological conditions. Exp Neurol. 1995;133265- 272Article
25.
Reddy  PHWilliams  MCharles  V  et al.  Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet. 1998;20198- 202Article
26.
Hodgson  JGAgopyan  NGutekunst  CA  et al.  A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron. 1999;23181- 192Article
27.
DiFiglia  MSapp  EChase  KO  et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;2771990- 1993Article
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