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

Strahlendorf, Jean C.; Box, Cathy; Attridge, Jennifer; Diertien, Janet; Finckbone, VelvetLee; Henne, W.; Medina, Margarita S.; Miles, Randy; Oomman, Sowmini; Schneider, Marcia; Singh, Hema; Veliyaparambil, Madhu; Strahlendorf, Howard K.

doi:10.1016/j.brainres.2003.09.048

Cited by 21 publications

(18 citation statements)

References 52 publications

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“…These features are peculiar of the type of neuronal cell death known as dark cell degeneration. This is characteristic of excitotoxic injury, in which excessive glutamate stimulation or excessive sensitivity to synaptic glutamate causes cellular toxicity (Barenberg et al, 2001;Strahlendorf et al, 2003). Intriguingly, this specific type of cell death has been recently described in mouse models of SCA7 and SCA5.…”

Section: Pcs Undergo Dark Degeneration In Afg3l2 Heterozygous Micementioning

confidence: 97%

“…These findings are consistent with an ongoing process of dark cell degeneration that has been documented in PCs exposed to excessive glutamate stimulation. The appearance of marked cytoskeletal changes in response to abusive AMPA receptor stimulation, coupled with increased intracellular Ca 2ϩ concentration, suggests activation of Ca 2ϩ -dependent cysteine proteases as the mechanism leading to darkening of the cytoplasm in degenerating PCs (Barenberg et al, 2001;Strahlendorf et al, 2003). Intriguingly, PC dark degeneration has been recently described in mouse models for SCA7 and SCA5.…”

Section: Dark Degeneration Of Pcs In Afg3l2 Heterozygous Micementioning

confidence: 99%

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Haploinsufficiency ofAFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Maltecca¹,

Magnoni²,

Cerri³

et al. 2009

J. Neurosci.

102

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Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m-AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like activity on the respiratory chain complexes. Despite coassembling in the same complex, mutations of either paraplegin or AFG3L2 cause two different neurodegenerative disorders. Indeed, mutations of paraplegin are responsible for a recessive form of hereditary spastic paraplegia, whereas mutations of AFG3L2 have been recently associated to a dominant form of spinocerebellar ataxia (SCA28). In this work, we report that the mouse model haploinsufficient for Afg3l2 recapitulates important pathophysiological features of the human disease, thus representing the first SCA28 model. Furthermore, we propose a pathogenetic mechanism in which respiratory chain dysfunction and increased reactive oxygen species production caused by Afg3l2 haploinsufficiency lead to dark degeneration of Purkinje cells and cerebellar dysfunction.

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Section: Pcs Undergo Dark Degeneration In Afg3l2 Heterozygous Micementioning

confidence: 97%

Section: Dark Degeneration Of Pcs In Afg3l2 Heterozygous Micementioning

confidence: 99%

Haploinsufficiency ofAFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Maltecca¹,

Magnoni²,

Cerri³

et al. 2009

J. Neurosci.

102

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“…These findings herein interpreted as characterizing ischaemic Purkinje neurons, could also be due to acti- vation of caspases and mitochondrial dysfunction [31], or hypoxia induced excitotoxic-type of dark cell degeneration [2]. Dark Purkinje dendritic arborisation and the degenerated parallel fibre and climbing Purkinje spines dendritic synapses could be related to the cognitive impairment and motor deficits of patients under study.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, a down-regulation of cell surface GABAB receptors has been postulated leading to diminished neuronal inhibition and contributing to excitotoxicity in cerebral ischaemia [23]. Cerebellar Purkinje neurons are selectively vulnerable to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepriopionic acid)-induced delayed neurotoxicity known as dark cell degeneration that is expressed as cytoplasmic and nuclear condensation, neuron shrinkage, and failure of physiology [31]. Sustained activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors leads to excitotoxic neuronal death as observed in stroke, brain trauma, and neurodegenerative disorders.…”

Section: Some Molecular Considerations On Peritumoural Cerebellar Iscmentioning

confidence: 99%

Ultrastructural pathology of human peritumoural oedematous cerebellar cortex

Castejón

2016

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“…Interestingly, other reports in the literature have demonstrated mitochondrial hyperpolarization associated with neuronal apoptosis (Poppe et al, 2001;Strahlendorf et al, 2003), but the most compelling observation about this phenomenon comes from studies of PBMCs obtained from patients with HIV-1. In this study, populations of PBMCs had hyperpolarized ΔΨm, which was associated with an activated T-cell phenotype more susceptible to apoptotic stimuli (Matarrese et al, 2003).…”

Section: Neuroprotective Strategies That Address Neuronal Bioenergeticsmentioning

confidence: 96%

Adjunctive therapies for HIV-1 associated neurologic disease

Perry¹,

Norman²,

Gelbard³

2005

neurotox res

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In the past decade we have seen a milder phenotype and decreased incidence of HIV-1 associated dementia (HAD), largely due to the widespread use of combination chemotherapy to reduce viral burden. However, the prevalence of neurologic disease in people living with HIV-1 has actually increased, raising significant concerns that new therapeutic strategies, directed at restoring neuronal and glial homeostasis and signaling in the central nervous system (CNS), as opposed to directly interfering with the life cycle of HIV-1, must be developed. In this review, we focus briefly on previous Phase 1 clinical trials for adjunctive (i.e., chemotherapeutic agents that do not have a primary antiretroviral mechanism of action) therapy in patients with HAD, followed by an overview of key molecular events in the neuropathogenesis of HAD, and then discuss in more detail our rationale for investigating the effects of therapeutic agents that restore impaired mitochondrial bioenergetics in the CNS. Specifically, we focus on agents that either work in part through K-ATP channels, present in both mitochondria and plasma membranes, and agents that work to weakly uncouple the respiratory capacity of the electron transport chain in mitochondria from ATP production. We propose these agents may be complementary to currently available antiretroviral agents and may significantly improve the capacity of CNS infected with HIV-1 to meet increased bioenergetic demands involved in normal synaptic communication.

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

Cited by 21 publications

References 52 publications

Haploinsufficiency ofAFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Haploinsufficiency ofAFG3L2, the Gene Responsible for Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration

Ultrastructural pathology of human peritumoural oedematous cerebellar cortex

Adjunctive therapies for HIV-1 associated neurologic disease

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