AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction

Jean Strahlendorf, Cathy Box, Jennifer Attridge, Janet Diertien, VelvetLee Finckbone, William M. Henne, Margarita S. Medina, Randy Miles, Sowmini Oomman, Marcia Schneider, Hema Singh, Madhu Veliyaparabil, Howard Strahlendorf

Research output: Contribution to journalArticle

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Abstract

Cerebellar Purkinje neurons (PNs) are selectively vulnerable to AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepriopionic acid)-induced delayed neurotoxicity known as dark cell degeneration (DCD) that is expressed as cytoplasmic and nuclear condensation, neuron shrinkage, and failure of physiology. The present study was initiated to determine whether AMPA-receptor-induced DCD in PNs is associated with Bax translocation to the mitochondria, cytochrome C release from the mitochondria, changes in mitochondrial potential, and activation of representative initiator and executor caspases that include caspase-9, caspase-3, and caspase-7. AMPA consistently and rapidly hyperpolarized mitochondria as reflected by an increase in MitoTracker Red CMS Ros fluorescence. Increases in Bax immunoreactivity were quantitatively and temporally variable and Bax failed to localize to mitochondria. Additionally, we observed a marked increase in immunoreactivity of cytochrome C although its release from mitochondria was not apparent. Mitochondrial membrane hyperpolarization and increases in cytochrome C immunoreactivity preceded caspase activation. Immunohistochemical analyses revealed the active form of caspases-3 and -9 were markedly and significantly increased in PNs following 30 μM AMPA, and caspase-9 activation preceded caspase-3. Increases in active caspase-7 immunoreactivity were less frequently encountered in PNs. Thus DCD shares some characteristics of apoptotic programmed cell death, but lacks typical mitochondrial pathophysiology associated with classic apoptosis. These findings suggest that AMPA-induced DCD is a form of active PCD that lies on a spectrum between classical apoptosis and passive necrosis.

Original languageEnglish (US)
Pages (from-to)146-159
Number of pages14
JournalBrain Research
Volume994
Issue number2
DOIs
StatePublished - Dec 24 2003

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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Purkinje Cells
Caspases
Mitochondria
Caspase 9
Cytochromes
Caspase 3
Caspase 7
Initiator Caspases
Apoptosis
AMPA Receptors
Mitochondrial Membranes
Cell Death
Necrosis
Fluorescence
Neurons
Acids

Keywords

  • AMPA
  • Caspases
  • Cerebellum
  • Excitotoxicity
  • Mitochondria

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction. / Strahlendorf, Jean; Box, Cathy; Attridge, Jennifer; Diertien, Janet; Finckbone, VelvetLee; Henne, William M.; Medina, Margarita S.; Miles, Randy; Oomman, Sowmini; Schneider, Marcia; Singh, Hema; Veliyaparabil, Madhu; Strahlendorf, Howard.

In: Brain Research, Vol. 994, No. 2, 24.12.2003, p. 146-159.

Research output: Contribution to journalArticle

Strahlendorf, J, Box, C, Attridge, J, Diertien, J, Finckbone, V, Henne, WM, Medina, MS, Miles, R, Oomman, S, Schneider, M, Singh, H, Veliyaparabil, M & Strahlendorf, H 2003, 'AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction', Brain Research, vol. 994, no. 2, pp. 146-159. https://doi.org/10.1016/j.brainres.2003.09.048
Strahlendorf, Jean ; Box, Cathy ; Attridge, Jennifer ; Diertien, Janet ; Finckbone, VelvetLee ; Henne, William M. ; Medina, Margarita S. ; Miles, Randy ; Oomman, Sowmini ; Schneider, Marcia ; Singh, Hema ; Veliyaparabil, Madhu ; Strahlendorf, Howard. / AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction. In: Brain Research. 2003 ; Vol. 994, No. 2. pp. 146-159.
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AU - Box, Cathy

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AU - Finckbone, VelvetLee

AU - Henne, William M.

AU - Medina, Margarita S.

AU - Miles, Randy

AU - Oomman, Sowmini

AU - Schneider, Marcia

AU - Singh, Hema

AU - Veliyaparabil, Madhu

AU - Strahlendorf, Howard

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AB - Cerebellar Purkinje neurons (PNs) are selectively vulnerable to AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepriopionic acid)-induced delayed neurotoxicity known as dark cell degeneration (DCD) that is expressed as cytoplasmic and nuclear condensation, neuron shrinkage, and failure of physiology. The present study was initiated to determine whether AMPA-receptor-induced DCD in PNs is associated with Bax translocation to the mitochondria, cytochrome C release from the mitochondria, changes in mitochondrial potential, and activation of representative initiator and executor caspases that include caspase-9, caspase-3, and caspase-7. AMPA consistently and rapidly hyperpolarized mitochondria as reflected by an increase in MitoTracker Red CMS Ros fluorescence. Increases in Bax immunoreactivity were quantitatively and temporally variable and Bax failed to localize to mitochondria. Additionally, we observed a marked increase in immunoreactivity of cytochrome C although its release from mitochondria was not apparent. Mitochondrial membrane hyperpolarization and increases in cytochrome C immunoreactivity preceded caspase activation. Immunohistochemical analyses revealed the active form of caspases-3 and -9 were markedly and significantly increased in PNs following 30 μM AMPA, and caspase-9 activation preceded caspase-3. Increases in active caspase-7 immunoreactivity were less frequently encountered in PNs. Thus DCD shares some characteristics of apoptotic programmed cell death, but lacks typical mitochondrial pathophysiology associated with classic apoptosis. These findings suggest that AMPA-induced DCD is a form of active PCD that lies on a spectrum between classical apoptosis and passive necrosis.

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