BALTIMORE—Patients with Parkinson’s disease need treatments that target cellular defects in addition to those that focus on dopaminergic neurons, according to research presented at the 134th Annual Meeting of the American Neurological Association.
Mutations in pink1 and parkin cause familial forms of Parkinson’s disease. A novel therapeutic target for Parkinson’s disease may be the modification of mitochondrial fusion and fission, which suppress defects due to a lack of pink1 and parkin, suggested Ming Guo, MD, PhD, an Associate Professor in Neurology and Molecular and Medical Pharmacology at the University of California, Los Angeles, David Geffen School of Medicine, and colleagues.
“In addition to motor symptoms such as tremor, slowness in movement, and rigidity, that we commonly know of, Parkinson’s disease patients also present with a variety of nonmotor symptoms, which include depression, obsessive-compulsive disorder, anxiety, and dementia, as well as some symptoms such as skin lesions, which are actually outside the nervous system,” Dr. Guo noted.
These nonmotor-dependent symptoms may be more debilitating, and are not usually responsive to dopamine replacement, which is the mainstay of Parkinson’s disease treatment. “In addition, dopamine replacement therapy ultimately fails in treating the motor symptoms. Therefore, we really need more research to understand the pathogenesis of Parkinson’s disease at the molecular and cellular level,” Dr. Guo said. “Studying functions of genes that mediate familial Parkinson’s disease provides us an unprecedented opportunity to understand Parkinson’s disease pathogenesis.”
Fruit Flies as a Model for Human Disease
Dr. Guo’s group used Drosophila in their studies. “Flies allow us to carry out in vivo studies,” Dr. Guo said. “It is [easy] to perform genetic screens and drug screens, and to identify the suppressors of disease mutant phenotype.”
Flies can also be used to study aging, sleep, learning and memory, aggression, and circadian rhythm. “A lot of these behaviors were originally thought to be distinctively human, yet we can still use flies to study the genetic basis of these behaviors,” Dr. Guo stated.
Dr. Guo and colleagues placed human pink1 and parkin genes in Drosophila. “We were delighted to see that the defects in flies lacking pink1 and parkin were eliminated,” Dr. Guo said. “This suggests that human and fly genes are functionally conserved, and they carry out similar roles.
In addition, human Parkinson’s disease patients also have similar mitochondrial defects to those seen in mutant Drosophila; thus, the studies in Drosophila are key to understanding the fundamental cellular defects in Parkinson’s disease patients.”
Dr. Guo’s group also found that the defects in Drosophila are present in multiple tissues beyond dopaminergic neurons. “This is reminiscent of Parkinson’s disease patients [that show] both motor phenotypes and nonmotor phenotypes.”
Pink1 and Parkin: A Common Genetic Pathway?
Dr. Guo’s laboratory found that flies lacking pink1 function show defects in mitochondria, the cellular organelles that are key in metabolism, energy production, cell death, and aging. “In addition, we found that the pink1 mutants show similar phenotypes to parkin mutants,” Dr. Guo noted.
By performing a series of elegant genetic studies, Dr. Guo’s group showed that pink1 and parkin function in a common genetic pathway, with pink1 positively regulating parkin.
Does Damaged Mitochondria Cause Parkinson's Disease?
Normal mitochondrial function is maintained by a constant balance between fusion and fission. “Remarkably, in the pink1 mutant background, when we are simultaneously increasing the level of fission or reducing the level of fusion, we see that most of the mitochondrial pathology and cell death associated with pink1 and parkin mutants are all rescued.”
Dr. Guo’s group proposed that the pink1 and parkin pathway promotes mitochondrial fission and/or inhibits fusion. “If we simultaneously help fusion, or increase the amount of fission, we are able to accomplish rescue both at the cellular level and at the animal behavioral level,” Dr. Guo explained.
The group also entertained the idea that the pink1 and parkin pathway promotes removal of damaged mitochondria through autophagy. “If this model is correct, Parkinson’s disease perhaps results from accumulation of damaged mitochondria,” Dr. Guo said. “This is an exciting hypothesis we are currently pursuing."
Emerging Themes
Dr. Guo and other colleagues suggest that at least for a portion of Parkinson’s disease, mitochondrial dysfunction is the central defect in disease pathogenesis. “In addition, it is important to know that more than one pathway is involved in causing Parkinson’s disease,” Dr. Guo stated. Multiple molecular pathways, including a pink1/parkin pathway that regulates mitochondrial integrity, and another pathway that regulates endo-lysosomal systems, may exist.
“By studying the genes involved in familial Parkinson’s disease, we think that Parkinson’s disease is a group of molecularly diverse disorders,” Dr. Guo said. Some are involved in mitochondrial dysfunction, and some in endo-lysosomal dysfunction.