MADISON, Wis.—Probing the role that astrocytes play in the progression of neurodegenerative diseases and resulting neuronal cell death, researchers at the University of Wisconsin-Madison (UWM) have discovered that increasing Nrf2 gene activity in astrocytes can completely block neuronal cell death in a mouse model of Parkinson's disease. According to the researchers, their findings strongly suggest that finding ways to boost the level of Nrf2 activation in the human brain could significantly impact the development and progression of Parkinson's disease.
With much of neurodegenerative disease research beginning to focus on the role that astrocytes, a major cell type in the brain, play in neuronal cell death in these diseases, scientists have hypothesized that neuronal death could actually be secondary to astrocyte dysfunction, as astrocytes can add up to about 70 percent of the cells found in our brains. "Sick" astrocytes are unable to support the neurons, and although they may survive, their inability to provide neurons with critical components for function and survival leads to the death of the neuron. According to Dr. Jeffrey Johnson, a pharmacy professor at UWM and a lead author of the study, finding ways to fix these sick astrocytes may yield great benefit in multiple neurodegenerative diseases.
"I guess you could consider me a very astrocyte-centric person," Johnson says. "Astrocytes way outnumber neurons and are found throughout the central nervous system. Neurons have always gotten the Academy Awards, but astrocyte dysfunction is becoming a central theme in neurodegenerative disease. If we can figure out how to fix a sick astrocyte, or even prevent it from getting sick, that could offer profound protection against almost all neurodegenerative diseases."
The major symptoms of Parkinson's, sluggish movement and tremors, have been traced to death of small numbers of nerve cells in the substantia nigra, a brain region that helps regulate movement. The researchers added extra copies Nrf2 in mouse models and dosed the mice with MPTP, a chemical that kills neurons in the substantia nigra. While the researchers expected to see a 20 to 40 percent reduction in cell death, to their surprise, adding extra copies of Nrf-2 neutralized the MPTP, resulting in the complete abolition of toxicity.
The researchers also observed that the Nrf2 pathway attacks the underlying mechanism of Parkinson's already identified in both the familial and sporadic forms of human disease, called oxidative stress. When astrocytes make Nrf-2, the protein attaches to their DNA, kick-starting activity in hundreds of genes that release chemicals that can protect nearby neurons from oxidation, a series of chemical reactions that can injure or kill cells.
"The astrocytes are also probably sucking up the bad stuff, thereby reducing the oxidative environment and stress on the neurons," says Johnson, adding that his laboratory is trying to identify those specific protective chemicals.
The research team is considering forming its own commercial company to pursue these findings, he says. Finally, in December, the scientists published a related study showing the positive effects of Nrf2 astrocytes in models of ALS, or Lou Gehrig's disease. The scientists will now study how Nrf2 astrocytes can modulate Huntington's and Alzheimer's disease, Johnson says.
"Rather than find a commercial partner, I think we will end up making one," Johnson says. "There has been a lot of interest, so my guess is that there will be some commercial group developed from this research group."
The study, Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte, was published Jan. 5 in the Proceedings of the National Academy of Sciences (PNAS). The study was funded by the National Institute of Environmental Health Sciences. DDN
With much of neurodegenerative disease research beginning to focus on the role that astrocytes, a major cell type in the brain, play in neuronal cell death in these diseases, scientists have hypothesized that neuronal death could actually be secondary to astrocyte dysfunction, as astrocytes can add up to about 70 percent of the cells found in our brains. "Sick" astrocytes are unable to support the neurons, and although they may survive, their inability to provide neurons with critical components for function and survival leads to the death of the neuron. According to Dr. Jeffrey Johnson, a pharmacy professor at UWM and a lead author of the study, finding ways to fix these sick astrocytes may yield great benefit in multiple neurodegenerative diseases.
"I guess you could consider me a very astrocyte-centric person," Johnson says. "Astrocytes way outnumber neurons and are found throughout the central nervous system. Neurons have always gotten the Academy Awards, but astrocyte dysfunction is becoming a central theme in neurodegenerative disease. If we can figure out how to fix a sick astrocyte, or even prevent it from getting sick, that could offer profound protection against almost all neurodegenerative diseases."
The major symptoms of Parkinson's, sluggish movement and tremors, have been traced to death of small numbers of nerve cells in the substantia nigra, a brain region that helps regulate movement. The researchers added extra copies Nrf2 in mouse models and dosed the mice with MPTP, a chemical that kills neurons in the substantia nigra. While the researchers expected to see a 20 to 40 percent reduction in cell death, to their surprise, adding extra copies of Nrf-2 neutralized the MPTP, resulting in the complete abolition of toxicity.
The researchers also observed that the Nrf2 pathway attacks the underlying mechanism of Parkinson's already identified in both the familial and sporadic forms of human disease, called oxidative stress. When astrocytes make Nrf-2, the protein attaches to their DNA, kick-starting activity in hundreds of genes that release chemicals that can protect nearby neurons from oxidation, a series of chemical reactions that can injure or kill cells.
"The astrocytes are also probably sucking up the bad stuff, thereby reducing the oxidative environment and stress on the neurons," says Johnson, adding that his laboratory is trying to identify those specific protective chemicals.
The research team is considering forming its own commercial company to pursue these findings, he says. Finally, in December, the scientists published a related study showing the positive effects of Nrf2 astrocytes in models of ALS, or Lou Gehrig's disease. The scientists will now study how Nrf2 astrocytes can modulate Huntington's and Alzheimer's disease, Johnson says.
"Rather than find a commercial partner, I think we will end up making one," Johnson says. "There has been a lot of interest, so my guess is that there will be some commercial group developed from this research group."
The study, Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte, was published Jan. 5 in the Proceedings of the National Academy of Sciences (PNAS). The study was funded by the National Institute of Environmental Health Sciences. DDN
