Why do neurons die in Parkinson’s disease?
Current thinking about Parkinson’s disease is that it’s a disorder of mitochondria, the energy-producing organelles inside cells, causing neurons in the brain’s substantia nigra to die or become impaired. A study from Children’s Hospital Boston now shows that genetic mutations causing a hereditary form of Parkinson’s disease cause mitochondria to run amok inside the cell, leaving the cell without a brake to stop them. Findings appear in the November 11 issue of Cell.
Mitochondrial movement is often a good thing, especially in neurons, which need to get mitochondria to cells’ periphery in order to fuel the axons and dendrites that send and receive signals. However, arresting this movement is equally important, says senior investigator Thomas Schwarz, PhD, of Children’s F.M. Kirby Neurobiology Center, since it allows mitochondria to be quarantined and destroyed when they go bad.
“Mitochondria, when damaged, produce reactive oxygen species that are highly destructive, and can fuse with healthy mitochondria and contaminate them, too,” Schwarz says. “It’s the equivalent of an environmental disaster in the cell.”
Studying neurons from fruit flies, rats and mice, as well as cultured human cells, Schwarz and colleagues provide the most detailed understanding to date of the effects of the gene mutations, which encode the proteins Parkin and PINK1. They demonstrate how these proteins interact with proteins responsible for mitochondrial movement - in particular Miro, which literally hitches a molecular motor onto the organelle.
Normally, when mitochondria go bad, PINK1 tags Miro to be destroyed by Parkin and enzymes in the cell, the researchers showed. When Miro is destroyed, the motor detaches from the mitochondrion. The organelle, unable to move, can then be disposed of: The cell literally digests it.
10 Signs of Depression In Parkinson’s
1. Excessive worrying
2. Persistent sadness
3. Crying
4. Loss of interest inusual activities and hobbies
5. Increased fatigue and lack of energy
6. Feelings of guilt
7. Loss of motivation
8. Complaints of aches and pains
9. Feelings of being a burden to loved ones
10. Ruminations about disability, death and
People with these symptoms should discuss them with a physician.
But when either PINK1 or Parkin is mutated, this containment system fails, leaving the damaged mitochondria free to move about the cell, spewing toxic compounds and fusing to otherwise healthy mitochondria and introducing damaged components.
The study’s findings are consistent with observed changes in mitochondrial distribution, transport and dynamics in other neurodegenerative diseases such as Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (Lou Gehrig’s disease), and Charcot-Marie-Tooth disease, the researchers note.
Although the team studied a rare hereditary form of Parkinson’s, the findings may shed light on what’s going on in the more common sporadic form of the disease, Schwarz says.
“Whether it’s clearing out damaged mitochondria, or preventing mitochondrial damage, the common thread is that there’s too much damage in mitochondria in a particular brain region,” he says.
Depression is one of the major, and most common, challenges for people living with Parkinson’s disease (PD). Everyone feels sad from time to time and it is normal to experience sadness and stress when faced with a difficult disease such as Parkinson’s. However, the sadness that is part of being human can become a significant problem if it crosses into the realm of clinical depression and is left untreated.
Just four years ago, when this article was originally written, health professionals, researchers and people living with or affected by PD were just beginning to recognize the extent of the prevalence of depression in Parkinson’s and itsimpact on daily life. Since that time, there has been a sharp and welcome increase in the awareness of depression as a common feature of the PD experience and of the importance of treating it. Not only that, but new research has also advanced our understanding of how to treat PD-related depression and has increased the range of the treatment options we have available.
At least 40 percent of people with PD experience clinical depression at some time during the disease. It may occur early or late in the course of Parkinson’s, and may wax and wane in severity. It causes personal suffering and also appears to intensify problemswith mobility and memory. A person with Parkinson’s, or his or her caregiver or physician, may at first dismiss the signs of depression because they assume that it is Parkinson’s that is causing the problem orbecause they assume it is normal to be depressed when faced with this illness. This can leadtofeelingsof helplessness and confusion, which may further exacerbate the problem.
While Schwarz sees potential in gene therapy to restore normal PINK1 or Parkin to neurons, he is more interested in the possibility of helping neurons flush out bad mitochondria or make enough new, healthy mitochondria to keep them viable. “We may need to do both,” he says.
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The study was funded by the Ellison Medical Foundation, the Hartman Foundation for Parkinson’s Research, the National Institutes of Health and a LSRF Novartis Fellowship. Xinnan Wang, PhD, of the F.M. Kirby Neurobiology Center at Children’s, was first author.
Children’s Hospital Boston is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Children’s research community. Founded as a 20-bed hospital for children, Children’s Hospital Boston today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children’s also is the primary pediatric teaching affiliate of Harvard Medical School.
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Erin Tornatore
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Children’s Hospital Boston