Defective Glia in the Drosophila Brain Degeneration Mutant drop-dead

Buchanan, Robert L.; Benzer, Seymour

doi:10.1016/0896-6273(93)90200-b

Cited by 144 publications

(129 citation statements)

References 47 publications

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“…From a mechanistic standpoint, it is widely appreciated that, in the uninjured CNS, nonreactive astrocytes are normally involved in the maintenance of the extracellular ionic environment and pH and the uptake of extracellular glutamate and interact with endothelial cells to induce and maintain the bloodbrain barrier (Kettenmann and Ransom, 1995). Moreover, astrocytes and related astroglia in other neural systems are known to provide nutritive, neurotrophic, and other supportive functions for neurons (Banker, 1980;Buchanan and Benzer, 1993;Tsacopoulos and Magistretti, 1996;Bush et al, 1998). However, determining the extent to which any particular combination of these functional attributes might explain the neuroprotective and trophic properties of "juvenile" neural precursor-derived astrocytes when cocultured with neurons in vitro will require further experimentation.…”

Section: Lenti-gdnf-infected Ns Increase the Survival Of Cotransplantmentioning

confidence: 99%

Neurospheres modified to produce glial cell line‐derived neurotrophic factor increase the survival of transplanted dopamine neurons

Ostenfeld

Tai

Martin

et al. 2002

J of Neuroscience Research

122

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Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival of dopamine neurons in a variety of in vitro and in vivo model systems. Therefore, it constitutes an important therapeutic protein with the potential to ameliorate dopamine neuronal degeneration in Parkinson's disease or to support dopamine neuronal replacement strategies. However, biophysical and practical considerations present obstacles for the direct delivery of the GDNF protein to CNS neurons. Here we show that rodent neural precursor cells isolated and expanded in culture as neurospheres (NS) can be genetically modified to express green fluorescent protein (GFP) or to release GDNF using lentiviral constructs. GDNF-NS increased the fibre outgrowth of primary embryonic dopamine neurons in cocultures, showing that the protein was released in biologically significant quantities. Furthermore, after transplantation into the 6-hydroxydopamine-lesioned rat striatum, GDNF-NS significantly increased the survival of cografted primary dopamine neurons. However, this was not reflected in behavioural recovery in these animals. We found that, by 6 weeks, few cells expressed GDNF or GFP, suggesting either that transgene expression was down-regulated over time or that the cells died. This may explain the initial effects on dopamine neuronal survival within the graft but the lack of long-term effect on subsequent fibre outgrowth and behaviour. Providing sustained levels of neural precursor-mediated transgene expression can be achieved following transplantation in the future; this approach may prove beneficial as an alternative therapeutic strategy in the cell-based management of Parkinson's disease.

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Section: Lenti-gdnf-infected Ns Increase the Survival Of Cotransplantmentioning

confidence: 99%

Neurospheres modified to produce glial cell line‐derived neurotrophic factor increase the survival of transplanted dopamine neurons

Ostenfeld

Tai

Martin

et al. 2002

J of Neuroscience Research

122

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“…To elucidate the underlying molecular pathways, Drosophila has been used successfully to model various neurodegenerative conditions, including tauopathy, polyglutamine repeat diseases, Parkinson's disease, and Alzheimer's disease (reviewed by Bonini and Fortini 2003). In complementary studies, forward genetic approaches have been used to identify genes required for age-dependent maintenance of neuronal viability (Buchanan and Benzer 1993;Kretzschmar et al 1997;Benzer 1997, 1999;Palladino et al 2002;Troulinaki and Tavernarakis 2005).…”

Section: G Enetic Factors Have Been Implicated In Virtuallymentioning

confidence: 99%

“…eag and Sh interact genetically in double mutants to produce flies that shake and have severe motor defects under all conditions owing to extreme hyperexcitability . As severe neurodegeneration is often associated with a strongly reduced life span (Buchanan and Benzer 1993;Kretzschmar et al 1997;Palladino et al 2002), we first determined the life span of eag, Sh, and sei mutants as well as eag Sh double mutants ( Figure 1, Table 1). Only eag Sh double mutants, which become severely uncoordinated with age, consistent with previous observations , showed significantly shortened life span (7 days 6 2.1, P , 0.001).…”

Section: Neuropathology In Kmentioning

confidence: 99%

Neuropathology in Drosophila Membrane Excitability Mutants

2006

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Mutations affecting ion channels and neuronal membrane excitability have been identified in Drosophila as well as in other organisms and characterized for their acute effects on behavior and neuronal function. However, the long-term effect of these perturbations on the maintenance of neuronal viability has not been studied in detail. Here we perform an initial survey of mutations affecting Na 1 channels and K 1 channels in Drosophila to investigate their effects on life span and neuronal viability as a function of age. We find that mutations that decrease membrane excitability as well as those that increase excitability can trigger neurodegeneration to varying degrees. Results of double-mutant interactions with dominant Na 1 /K 1 ATPase mutations, which themselves cause severe neurodegeneration, suggest that excitotoxicity owing to hyperexcitability is insufficient to explain the resultant phenotype. Although the exact mechanisms remain unclear, our results suggest that there is an important link between maintenance of proper neuronal signaling and maintenance of long-term neuronal viability. Disruption of these signaling mechanisms in any of a variety of ways increases the incidence of neurodegeneration.

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“…x3 is an X-chromosomal recessive mutation that causes dramatic behavioral defect, brain degeneration and an extremely short lifespan (Buchanan & Benzer, 1993). Males heterozygous for rpd3 P-UTR are hypomorphic for rpd3 and long lived (Rogina et al, 2002).…”

Section: X3mentioning

confidence: 99%