PNAS: Polyamine pathway plays a role in Parkinson's disease pathogenesis
Findings from human patients, yeast and a mouse model imply that defects in polyamine pathway play a role in Parkinson's disease pathogenesis, suggesting that existing drugs may be able to slow progression of the disease, according to a study published Sept. 13 in an early online edition of Proceedings of the National Academy of Sciences.
"The most exciting thing about the finding is that it opens up the possibility of using a whole class of drugs that is already available," said the study's senior author Scott A. Small, MD, the Herbert Irving associate professor of neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center in New York City. "Additionally, since polyamines can be found in blood and spinal fluid, this may lead to a test that could be used for early detection of Parkinson's," added Small.
Using high resolution functional magnetic resonance imaging, Nicole Lewandowski, PhD, a post-doctoral research scientist in Small's lab, identified a region in the brainstem of patients with Parkinson's that was consistently less active in patients than in healthy control subjects. Next, using brain tissue from deceased patients with Parkinson's, the researchers looked for proteins that could potentially explain the brainstem imaging differences and identified a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1).
"Because SAT1 is known as an enzyme that helps break down polyamines, and previous research had shown that Parkinson's patients have high levels of polyamines in their brains, we hypothesized that SAT1 and polyamines are involved in the development of Parkinson's disease," said Small.
To validate the finding, three separate studies--in yeast, mice and people--were performed by the researchers. The yeast studies found that yeast cells, engineered to produce the toxic Parkinson's protein, die more quickly in the presence of increasing polyamine levels. In the mice studies, a link was established among SAT1, polyamines, and Parkinson's toxins in a mammalian brain. These experiments also revealed that drugs that target SAT1 may be able to slow down the progression of Parkinson's disease. Using drugs that increase SAT1 activity and therefore lower polyamine levels, researchers in the lab of Eliezer Masliah, MD, professor of neurosciences and pathology at the University of California, San Diego School of Medicine, La Jolla, Calif., found a decrease in Parkinson's toxins and the damage which they cause within brain regions affected by the disease.
Genetic studies in patients with Parkinson's provided further evidence that polyamines may help drive Parkinson's disease in people. After examining the SAT1 gene in 92 patients with Parkinson's and additional genotyping in a further 797 subjects (389 PD patients and 408 controls), Lorraine Clark, PhD, assistant professor of clinical pathology and cell biology, together with Karen Marder, MD, the Sally Kerlin Professor of Neurology in the Sergievsky Center and in the Taub Institute, uncovered a novel genetic variant that was found exclusively in the study's patients with Parkinson's but not in controls.
Small and colleagues are now testing current polyamine-lowering drugs to see if the compounds pass through the blood-brain barrier, or if they can be altered to do so.
The findings have immediate clinical implications, according to Small and colleagues. First, because polyamines can be measured in cerebral spinal fluid and blood, serological analysis might be able to detect polyamine abnormalities and can be used for early detection of Parkinson's disease and for monitoring therapeutic interventions. Second, a number of pharmacological agents have already been developed that enhance the function of SAT1 and polyamine metabolism, concluded Small and colleagues.
"The most exciting thing about the finding is that it opens up the possibility of using a whole class of drugs that is already available," said the study's senior author Scott A. Small, MD, the Herbert Irving associate professor of neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center in New York City. "Additionally, since polyamines can be found in blood and spinal fluid, this may lead to a test that could be used for early detection of Parkinson's," added Small.
Using high resolution functional magnetic resonance imaging, Nicole Lewandowski, PhD, a post-doctoral research scientist in Small's lab, identified a region in the brainstem of patients with Parkinson's that was consistently less active in patients than in healthy control subjects. Next, using brain tissue from deceased patients with Parkinson's, the researchers looked for proteins that could potentially explain the brainstem imaging differences and identified a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1).
"Because SAT1 is known as an enzyme that helps break down polyamines, and previous research had shown that Parkinson's patients have high levels of polyamines in their brains, we hypothesized that SAT1 and polyamines are involved in the development of Parkinson's disease," said Small.
To validate the finding, three separate studies--in yeast, mice and people--were performed by the researchers. The yeast studies found that yeast cells, engineered to produce the toxic Parkinson's protein, die more quickly in the presence of increasing polyamine levels. In the mice studies, a link was established among SAT1, polyamines, and Parkinson's toxins in a mammalian brain. These experiments also revealed that drugs that target SAT1 may be able to slow down the progression of Parkinson's disease. Using drugs that increase SAT1 activity and therefore lower polyamine levels, researchers in the lab of Eliezer Masliah, MD, professor of neurosciences and pathology at the University of California, San Diego School of Medicine, La Jolla, Calif., found a decrease in Parkinson's toxins and the damage which they cause within brain regions affected by the disease.
Genetic studies in patients with Parkinson's provided further evidence that polyamines may help drive Parkinson's disease in people. After examining the SAT1 gene in 92 patients with Parkinson's and additional genotyping in a further 797 subjects (389 PD patients and 408 controls), Lorraine Clark, PhD, assistant professor of clinical pathology and cell biology, together with Karen Marder, MD, the Sally Kerlin Professor of Neurology in the Sergievsky Center and in the Taub Institute, uncovered a novel genetic variant that was found exclusively in the study's patients with Parkinson's but not in controls.
Small and colleagues are now testing current polyamine-lowering drugs to see if the compounds pass through the blood-brain barrier, or if they can be altered to do so.
The findings have immediate clinical implications, according to Small and colleagues. First, because polyamines can be measured in cerebral spinal fluid and blood, serological analysis might be able to detect polyamine abnormalities and can be used for early detection of Parkinson's disease and for monitoring therapeutic interventions. Second, a number of pharmacological agents have already been developed that enhance the function of SAT1 and polyamine metabolism, concluded Small and colleagues.