October 6, 2009
Enzyme may be a key to Alzheimer's-related cell death
WEST LAFAYETTE, Ind. - |
Sandra Rossie, a professor of biochemistry, found that increasing the amount of protein phosphatase 5, or PP5, in rat neural cells resulted in less cell death associated with reactive oxygen species, which chemically damage cell molecules. Conversely, decreasing PP5 caused greater cell death. The results of Rossie's study are published in the early online version of The Journal of Neurochemistry.
Alzheimer's, a degenerative neurological disease affecting around 5 million people, results in memory loss and dementia. One theory on the cause of Alzheimer's is that overproduction of certain forms of amyloid beta protein by neurons leads to the generation of reactive oxygen species, which activate stress pathways.
"If stress pathways remain active for a prolonged period, the cell will die," Rossie said.
Rossie's lab found that PP5 overexpression prevents neuronal death by amyloid beta and shuts off the stress pathways. When reactive oxygen that wasn't created by amyloid beta was used on the cells, the results were the same. In contrast, neurons with reduced PP5 are more sensitive to death caused by amyloid beta.
"That suggests to us that PP5 protects neurons from cell death induced by reactive oxygen species, not just the presence of amyloid beta," Rossie said. "This means that PP5 may protect against other health problems involving reactive oxygen species as well, such as stroke and heart attacks."
It is possible, Rossie said, that finding a way to increase PP5 activity could help prevent the loss of neurons by amyloid beta.
Rossie said PP5 also could play a role in inhibiting other responses of neurons to amyloid beta. Her lab will work to determine which pathways PP5 affects, and which of those is most responsible for neural protection by PP5.
The National Institutes of Health funded Rossie's research.
Writer: Brian Wallheimer, 765-496-2050, bwallhei@purdue.edu
Source: Sandra Rossie, 765-494-3112, rossie@purdue.edu
Ag Communications: (765) 494-8415;
Steve Leer, sleer@purdue.edu
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PHOTO CAPTION:
Sandra Rossie found that an enzyme blocks a mechanism that can lead to neural cell death. (Purdue Agricultural Communication photo/Tom Campbell)
A publication-quality photo is available at https://www.purdue.edu/uns/images/+2009/rossie-enzyme.jpg
Protein phosphatase 5 protects neurons against amyloid-toxicity
Efrain Sanchez-Ortiz, Byoung Kwon Hahm, David L. Armstrong and Sandra Rossie
Amyloid-(A) is thought to promote neuronal cell loss in Alzheimer's disease, in part through the generation of reactive oxygen species (ROS) and subsequent activation of mitogen-activated protein kinase (MAPK) pathways. Protein phosphatase 5 (PP5) is a ubiquitously expressed serine/threonine phosphatase, which has been implicated in several cell stress response pathways and shown to inactivate MAPK pathways through key dephosphorylation events. Therefore, we examined whether PP5 protects dissociated embryonic rat cortical neurons in vitro from cell death evoked by A. As predicted, neurons in which PP5 expression was decreased by small-interfering RNA treatment were more susceptible to A toxicity. In contrast, over-expression of PP5, but not the inactive mutant, PP5(H304Q), prevented MAPK phosphorylation and neurotoxicity induced by A. PP5 also prevented cell death caused by direct treatment with H2O2, but did not prevent A-induced production of ROS. Thus, the neuroprotective effect of PP5 requires its phosphatase activity and lies downstream of A-induced generation of ROS. In summary, our data indicate that PP5 plays a pivotal neuroprotective role against cell death induced by A and oxidative stress. Consequently, PP5 might be an effective therapeutic target in Alzheimer's disease and other neurodegenerative disorders in which oxidative stress is implicated.
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