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Neuronal cultured cell deaths due to withdrawl of GDNF and BDNF

Implications for the Amgen aborted study?

http://www.eurekalert.org/pub_releas...-ntf071608.php
Neuronal Death Path
Li-ying Yu, Mart Saarma, and Urmas Arumäe

Programmed cell death pathways are generally divided into two broad categories: the intrinsic pathway, in which cellular stress (e.g., oxidative stress) leads to release of cytochrome c from mitochondria, which leads to activation of caspase-9, which activates effector caspases that degrade cellular proteins; and the extrinsic pathway, in which extracellular ligands bind to death receptors, which activate Fas-activated death domain (FADD) protein, which leads to activation of caspase-8, which activates effector caspases. This week, Yu et al. describe the apoptosis pathway activated by withdrawal of GDNF and BDNF from cultured midbrain dopaminergic neurons. The normal intrinsic pathway was not involved, because cytochrome c was not released from mitochondria. Nonetheless, caspase-9 was involved. Death-receptor pathways were also involved, because blocking FADD or caspase-8 prevented apoptosis. Interestingly, this apoptosis pathway is different than that induced by withdrawal of GDNF from sympathetic neurons.

this could be helpful

Madelyn,
In a few words to answer your question about implications - I would think so. The abrupt withdrawal of GDNF has been argued to have been the cause of the infamous monkey lesions. But the dosage was extremely high.

Am I under the correct assumption to interpret this article as implying that withdrawal of GDNF could have increased neuronal death in the participants?

paula

I'm no expert, but . . .

I only read that the pathway of apoptosis (cell death) is "different" from the natural path of destruction when GDNF deprivation is introduced.

I didn't have time to extensively check out this researcher, but here is the latest abstract from Pub Med:

Quote:

Yu LY, Arumäe U.
Institute of Biotechnology, University of Helsinki, FIN-00014, Helsinki, Finland.

Death pathways in the apoptotic neurons are mostly studied by manipulating the levels of apoptosis-related proteins and counting the survival/death of affected neurons. Such assays are, however, technically complicated. We developed a transfection-survival assay for cultured embryonic dopaminergic (DA) neurons induced to die by deprivation of glial cell line-derived neurotrophic factor (GDNF). The calcium phosphate co-precipitation technique was used to transfect DA neurons. Microisland cultures and co-transfected enhanced green fluorescent protein allowed direct counting of transfected neurons from the same cultures at the beginning and the end of GDNF deprivation, whereas post hoc subtraction of tyrosine hydroxylase-negative neurons allowed exclusion of transfected non-DA neurons. Overexpression of dominant-negative mutant of caspase-6 significantly blocked the death of GDNF-deprived DA neurons. Thus, we have found a tool not only to transfect the neurons dissociated from midbrain, but also to analyze the apoptotic proteins particularly in DA neurons.

I think this just says they found a new way to look at the proteins and neurons involved in cell death in dopaminergic neurons by depriving them GDNF. This cell death thing (apoptosis) is heavy technical stuff, but here's a poster for those of you who can read the language:
http://www.emdbiosciences.com/docs/d...s_poster_E.pdf

As I see it, the benefit of what these authors have found could be very helpful in stem cell research and gene therapy (among other strategies studied).