Granule neuron DNA damage following deafferentation in adult rats cerebellar cortex: a lesion model

Borsello, Tiziana; Luzio, A. Di; Ciotti, Maria Teresa; Calissano, Pietro; Galli, Cinzia

doi:10.1016/s0306-4522(99)00397-8

Cited by 25 publications

(15 citation statements)

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“…To test this hypothesis, we performed preliminary experiments on primary cerebellar granule neurons (CGNs) partially deprived (5.0 mM) of high depolarizing concentrations (25 mM) of extracellular KCl, a culture condition required for their in vitro survival. 29 We found that apoptotic death occurred after K þ starvation -possibly because it mimics the in vivo mossy fibers deafferentation induced by axotomy 30 -and that this was reversible up to 4-8 h after treatment with high concentration of KCl, forskolin and IGF-1. 29 Neuronal loss was characterized by de novo RNA/protein synthesis and coordinated gene expression, 31 nuclear condensation and fragmentation, decrease of intracellular free calcium levels 32 and by an imbalance of the physiological APP metabolism toward the amyloidogenic noxious counterpart.…”

Section: Amyloidogenesis and Apoptosismentioning

confidence: 93%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

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Section: Amyloidogenesis and Apoptosismentioning

confidence: 93%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

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“…In addition, this type of cellular degradation appears to be involved in neurodegenerative disorders, such as Parkinson's disease (Mochizuki et al, 1996) and Alzheimer's disease (Smale et al, 1995), as well as in acute injury-related neuronal damage, such as lesions (Borsello et al, 2000), spinal cord trauma (Li et al, 1996;Crowe et al, 1997), and stroke (Isenmann et al, 1998). Apoptosis is a genetically regulated process that is characterized by several hallmark morphological changes.…”

mentioning

confidence: 98%

“…This form of cell death occurs following target removal in the rat dentate gyrus (Cameron and Gould, 1996), after injuries in the teleost cerebellum (Zupanc et al, 1998), and in the rat cerebellar cortex following deafferentation (Borsello et al, 2000). Removal of the OB in adult rat results in the induction of cell death in the piriform cortex (Heimer and Kalil, 1978).…”

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confidence: 99%

Apoptosis following peripheral sensory deafferentation in the olfactory bulb of adult zebrafish

VanKirk

Byrd

2002

J of Comparative Neurology

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Removal of the olfactory organ in adult zebrafish results in a significant decrease in volume of the ipsilateral olfactory bulb. The current study investigated the potential role of apoptosis in this phenomenon. It was hypothesized that cells in the adult olfactory bulb normally undergo minimal apoptosis and that apoptosis increases upon removal of sensory stimulation. By using both the terminal transferase-mediated deoxyuridine nick-end labeling method and bis-benzimide labeling, the current study showed that, in the normal adult olfactory bulb, cells exhibiting apoptotic profiles were scarce and were localized to the outer layers of the bulb. However, in deafferented animals, there was a significant increase in the number of apoptotic cells. The apoptotic response occurred in two phases and was confined to the rostral half of the bulb. The first phase of cell death peaked at 1 hour postsurgery. These apoptotic profiles appeared to be primarily nonneuronal in nature, in that they exhibited no immunohistochemical labeling to the neuron-specific protein Hu. The second phase of cell death peaked at 24 hours and declined to normal levels by 1 week. At the 24 hour time point, only a fraction of the apoptotic cells was neuronal in nature. Thus, apoptosis of nonneuronal and neuronal elements accounts for at least part of the deafferentation-induced volume decrease in the zebrafish olfactory bulb. This model of anterograde transneuronal degeneration will be useful in elucidating the afferent signals involved in survival and maintenance of mature brain neurons.

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“…In the lurcher mouse, cerebellar granule neurons die in response to the death of their targets, Purkinje neurons (Wetts and Herrup 1982). If the afferent activity to granule neurons is eliminated by mossy fiber axotomy, they undergo massive apoptosis (Borsello et al 2000). These findings have been mimicked in vitro.…”

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confidence: 99%

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Harris¹,

Maroney²,

Johnson

2002

Journal of Neurochemistry

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Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when switched to medium containing 5 mM potassium, a stimulus mimicking deafferentation. This cell death can be blocked by genetic deletion of Bax, a member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of macromolecular synthesis or expression of dominant-negative c-jun. These observations suggest that Bax activation is the result of c-jun target gene(s) up-regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell neuronal apoptosis in response to low potassium were investigated using CEP-1347 (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection of potassium-serum-deprived granule cells, but such neuroprotection was not long term. The incomplete protection was not due to incomplete blockade of the JNK signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA and protein were completely blocked by CEP-1347. Following potassium-serum deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347. Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition of caspases and MLKs has additive, not synergistic, effects on survival. A lack of synergism was also seen with the p38 inhibitor SB203580, indicating that the neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38 activation. Activation of the JNK signaling pathway seems to be a key event in granule cell apoptosis, but these neurons cannot survive long term in the absence of sustained PI3 kinase signaling. Neuronal survival is controlled in vivo by both retrograde signaling from neuronal targets as well as anterogradely via synaptic input. Cerebellar granule neurons are one such population whose survival is regulated by retrograde and anterograde signaling both in vivo and in vitro. In the lurcher mouse, cerebellar granule neurons die in response to the death of their targets, Purkinje neurons (Wetts and Herrup 1982). If the afferent activity to granule neurons is eliminated by mossy fiber axotomy, they undergo massive apoptosis (Borsello et al. 2000). These findings have been mimicked in vitro. Target-derived neurotrophic factors such as brain-derived growth factor (BDNF) and insulin-like growth factor (IGF)-1 promote the survival of cerebellar granule cells (Lindholm et al. 1993;Miller et al. 1997b). These neurons also undergo massive cell death when deafferentation is mimicked by removing the survival stimulus provided by depolarizing levels of potassium (Gallo et al. 1987). Abbreviations used: ASK, apoptosis signal regulating kinase 1; BAF, boc-aspartyl(OMe)-fluoromethylketone; BME, b-mercaptoethanol; CMV, cytomegalovirus; DEVD-amc, DEVD-aminomethylcoumarin; DIV, days in vitro; DTT, dithiothreitol; IP3, inositol-1,4,5-triphosphate; JNK, c-Jun N-terminal kinase; JNKKK, JNK kinase kinase; K5 ) S, buffer containing 5 mM KCl without serum; K25 + S, buf...

show abstract

Granule neuron DNA damage following deafferentation in adult rats cerebellar cortex: a lesion model

Cited by 25 publications

References 50 publications

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

Apoptosis following peripheral sensory deafferentation in the olfactory bulb of adult zebrafish

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

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