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Study suggests loss of 2 types of neurons -- not just 1 -- triggers Parkinson's symptoms
August 14, 2007New evidence indicates that the loss of two types of brain cells--not just one as previously thought--may trigger the onset of symptoms associated with Parkinson's disease.
The evidence, based on mouse models, shows a link between the loss of both norepinephrine and dopamine neurons and the delayed onset of symptoms associated with Parkinson's disease. It was originally thought that the loss of only dopamine neurons triggered symptoms. Dopamine is a neurotransmitter critical for coordinating movement.
Results of the study by Emory scientists, along with the University of Georgia, will appear in the Proceedings of the National Academy of Sciences, Early Edition online during the week of Aug. 13-17 and in the Aug. 21 print edition.
The research was conducted by Karen Rommelfanger, graduate student in the laboratory of David Weinshenker, PhD, assistant professor of human genetics in Emory University School of Medicine and Gary Miller, PhD, associate professor in Emory's Rollins School of Public Health. The team also included Gaylen Edwards and Kimberly Freeman at the University of Georgia.
Parkinson's disease affects motor coordination and is characterized by symptoms such as tremors of hands, arms, legs, jaw and face; rigidity or stiffness of limbs and trunk; bradykinesia, or slowness of movement; and postural instability. The disease most often occurs in those over 50.
"People don't start showing symptoms of Parkinson's disease until about 80 percent of their dopamine neurons are gone, which is when you cross some sort of threshold. Our study looked at what happens while the dopamine neurons are dying and people still appear fine, says Dr. Weinshenker. "The lack of symptoms until the death of most of the dopamine neurons suggested the existence of a system that can temporarily compensate for the loss of the dopamine."
"The dogma in the field is that Parkinson's disease involves a selective loss of dopamine neurons. The truth is, if you look at postmortem Parkinson's disease brains, you will see that both dopamine and norepinephrine neurons are gone," Dr. Weinshenker explains. "We know that norepinephrine is important for regulating the activity of dopamine neurons, so we suspected that the dopamine neurons and the norepinephrine neurons function in concert. As the dopamine neurons start dying, the norepinephrine neurons compensate by signaling the surviving dopamine cells to dramatically increase their activity and the output of dopamine. Eventually, the norepineprhine neurons die, the surviving dopamine neurons lose their ability to release extra dopamine, and symptoms start to appear."
To test their hypothesis, the researchers gave healthy, one-year-old mice the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) at a dose that kills about 80 percent of the dopamine cells, but observed no motor impairments in the mice. Surprisingly, when they tested mice unable to synthesize norepinephrine and that have trouble releasing dopamine properly, they observed symptoms of Parkinson's disease including resting tremor, hunched posture and deficits in coordinated movement. These results indicate that having a normal complement of dopamine neurons is not enough for normal motor function; norepinephrine also needs to be present to ensure proper dopamine release.
"Although there are no cures for Parkinson's disease, some moderately effective treatments are available, but most target the dopamine neurons only and are effective for only a limited amount of time. In light of this study, it's quite possible that simultaneously treating both the dopamine and norepinephrine loss could further ameliorate the symptoms of Parkinson's disease," says Dr. Weinshenker.
Emory University
The research was conducted by Karen Rommelfanger, graduate student in the laboratory of David Weinshenker, PhD, assistant professor of human genetics in Emory University School of Medicine and Gary Miller, PhD, associate professor in Emory's Rollins School of Public Health. The team also included Gaylen Edwards and Kimberly Freeman at the University of Georgia.
Parkinson's disease affects motor coordination and is characterized by symptoms such as tremors of hands, arms, legs, jaw and face; rigidity or stiffness of limbs and trunk; bradykinesia, or slowness of movement; and postural instability. The disease most often occurs in those over 50.
"People don't start showing symptoms of Parkinson's disease until about 80 percent of their dopamine neurons are gone, which is when you cross some sort of threshold. Our study looked at what happens while the dopamine neurons are dying and people still appear fine, says Dr. Weinshenker. "The lack of symptoms until the death of most of the dopamine neurons suggested the existence of a system that can temporarily compensate for the loss of the dopamine."
"The dogma in the field is that Parkinson's disease involves a selective loss of dopamine neurons. The truth is, if you look at postmortem Parkinson's disease brains, you will see that both dopamine and norepinephrine neurons are gone," Dr. Weinshenker explains. "We know that norepinephrine is important for regulating the activity of dopamine neurons, so we suspected that the dopamine neurons and the norepinephrine neurons function in concert. As the dopamine neurons start dying, the norepinephrine neurons compensate by signaling the surviving dopamine cells to dramatically increase their activity and the output of dopamine. Eventually, the norepineprhine neurons die, the surviving dopamine neurons lose their ability to release extra dopamine, and symptoms start to appear."
To test their hypothesis, the researchers gave healthy, one-year-old mice the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) at a dose that kills about 80 percent of the dopamine cells, but observed no motor impairments in the mice. Surprisingly, when they tested mice unable to synthesize norepinephrine and that have trouble releasing dopamine properly, they observed symptoms of Parkinson's disease including resting tremor, hunched posture and deficits in coordinated movement. These results indicate that having a normal complement of dopamine neurons is not enough for normal motor function; norepinephrine also needs to be present to ensure proper dopamine release.
"Although there are no cures for Parkinson's disease, some moderately effective treatments are available, but most target the dopamine neurons only and are effective for only a limited amount of time. In light of this study, it's quite possible that simultaneously treating both the dopamine and norepinephrine loss could further ameliorate the symptoms of Parkinson's disease," says Dr. Weinshenker.
Emory University
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