Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease

Turmaine, Mark; Raza, Aysha; Mahal, Amarbirpal; Mangiarini, Laura; Bates, Gillian P.; Davies, Stephen

doi:10.1073/pnas.110078997

Cited by 398 publications

(296 citation statements)

References 34 publications

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“…Several studies suggest that amyloid aggregate toxicity can trigger apoptotic and/or necrotic cell death [2,3,16,44,61]. It is generally believed that cell death associated with protein aggregates begins with stimulation of the apoptotic response, although recent data show necrotic rather than apoptotic death in some cases [33,65,67,72]. The biochemistry of cell death following exposure to the toxic amyloid aggregates is still under investigation, but our results support these suggestions.…”

Section: Discussionsupporting

confidence: 77%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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Much experimental evidence suggests that an imbalance in cellular redox status is a major factor in the pathogenesis of Alzheimer's disease (AD). Our previous data showed a marked increase in membrane lipoperoxidation in primary fibroblasts from familial AD (FAD) patients. In the present study, we demonstrate that when oligomeric structures of A␤ 1-40 and A␤ 1-42 are added to the culture media, they accumulate quicker near the plasma membrane, and are internalized faster and mostly in APPV717I fibroblasts than in age-matched healthy cells; this results in an earlier and sharper increase in the production of reactive oxygen species (ROS). Higher ROS production leads in turn to an increase in membrane oxidative-injury and significant impairment of cellular antioxidant capacity, giving rise to apoptotic cascade activation and finally to a necrotic outcome. In contrast, healthy fibroblasts appear more resistant to amyloid oxidative-attack, possibly as a result of their plasma membrane integrity and powerful antioxidant capacity. Our data are consistent with increasing evidence that prefibrillar aggregates, compared to mature fibrils, are likely the more toxic species of the peptides. These findings provide compelling evidence that cells bearing increased membrane lipoperoxidation are more susceptible to aggregate toxicity as a result of their reduced ability to counteract amyloid oligomeric attack.

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Section: Discussionsupporting

confidence: 77%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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“…The precise cell death pathway may also vary between disorders. For example, although the animal model of juvenile Huntington disease included in this analysis showed apoptotic neurodegeneration, models containing large numbers of glutamine repeats show evidence of nonapoptotic cell death 28 . Autophagy is a caspase-independent mode of cell death that seems to be involved in some neurodegenerations 15 , but both caspases and autophagy can be simultaneously activated in dying cells, and so different cell types and contexts may trigger the use of caspases, the ubiquitin-proteasome pathway, autophagy or perhaps other mechanisms to destroy the cell 4,15 .…”

Section: Interpreting Allometric Differencesmentioning

confidence: 96%

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

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We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steadystate RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.Cell death in inherited neurodegenerative disorders most commonly occurs by apoptosis 1-4 . The evidence is often indirect and inferred on the basis of characteristic morphological changes, such as chromatin compaction and cell shrinkage, or evidence of caspase activation, but in many cases it is more reliably based on multiple lines of evidence [1][2][3][4] . Caspase-independent cell death also occurs, although the precise mechanisms are less well understood and evidence that this occurs in inherited neurodegenerations is sparse. In these disorders, cell death occurs with a probability that is constant through part or all of the adult lifespan, consistent with a steady-state (one-hit or exponential kinetics) rather than a cumulative damage model 5,6 . The retina is a particularly well understood model of neurodegeneration. Mutations in more than 100 genes are known to cause neurodegeneration of retinal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell 7-9 .Two main pathways lead to the activation of cysteine proteases or caspases that execute the apoptotic death program [10][11][12] . The extrinsic pathway involves cell-surface signaling complexes (e.g., Fas or FasL), which trigger the cell death cascade by activating caspase 8 and downstream caspases. The intrinsic, or mitochondrial, pathway controls activation of caspase 9, through the adaptor molecule Apaf-1, by regulating release of cytochrome c from mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family and various stress and survival signals regulate the release of cytochrome c. Proapoptotic signals can also release proteins such as Smac and Omi, which antagonize IAP (inhibitor of apoptosis) proteins to activate cell death caspases, from the mitochondrial intermembrane space.Evidence from animal models of human photoreceptor degeneration suggests that the mitochondrial, rather than the extrinsic, cell death pa...

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“…Although pcd has often been equated with apoptosis, it has become increasingly clear that nonapoptotic forms of pcd also exist. [1][2][3][4][5][6][7][8][9][10][11][12][13] For example, certain developmental cell deaths, such as 'autophagic' cell death [1][2][3][4][5] and 'cytoplasmic' cell death, 2,4,6-9 do not resemble apoptosis. Furthermore, neurodegenerative diseases such as Huntington's disease and amyotrophic lateral sclerosis demonstrate neuronal cell death that does not fulfill the criteria for apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, neurodegenerative diseases such as Huntington's disease and amyotrophic lateral sclerosis demonstrate neuronal cell death that does not fulfill the criteria for apoptosis. 10,11 Ischemiainduced cell deaths may also display a nonapoptotic morphology, referred to as 'oncosis.' 13 The biochemical mechanisms underlying these alternative morphological forms of cell death remain incompletely defined.…”

Section: Introductionmentioning

confidence: 99%

Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix

et al. 2004

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Programmed cell death (pcd) may take the form of apoptotic or nonapoptotic pcd. Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the mediators of nonapoptotic cell death programs are much less well characterized. Here, we report that paraptosis, an alternative, nonapoptotic cell death program that may be induced by the insulin-like growth factor I receptor (among other inducers), is mediated by mitogen-activated protein kinases (MAPKs) and inhibited by AIP-1/Alix. The inhibition by AIP-1/Alix is specific for paraptosis since apoptosis was not inhibited. Caspases were not activated in this paradigm, nor were caspase inhibitors effective in blocking cell death. However, insulinlike growth factor I receptor (IGFIR)-induced paraptosis was inhibited by MEK-2-specific inhibitors and by antisense oligonucleotides directed against c-jun N-terminal kinase-1 (JNK-1). These results suggest that IGFIR-induced paraptosis is mediated by MAPKs, and inhibited by AIP-1/Alix.

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Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease

Cited by 398 publications

References 34 publications

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Lifespan and mitochondrial control of neurodegeneration

Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix

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