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.
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.
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.
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. For more information about research and clinical innovation at Children's, visit: http://vectorblog.org
Erin Tornatore | EurekAlert!
Family of crop viruses revealed at high resolution for the first time
15.10.2019 | John Innes Centre
Receptor complexes on the assembly line
15.10.2019 | Albert-Ludwigs-Universität Freiburg im Breisgau
Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich have explored the initial consequences of the interaction of light with molecules on the surface of nanoscopic aerosols.
The nanocosmos is constantly in motion. All natural processes are ultimately determined by the interplay between radiation and matter. Light strikes particles...
Particles that are mere nanometers in size are at the forefront of scientific research today. They come in many different shapes: rods, spheres, cubes, vesicles, S-shaped worms and even donut-like rings. What makes them worthy of scientific study is that, being so tiny, they exhibit quantum mechanical properties not possible with larger objects.
Researchers at the Center for Nanoscale Materials (CNM), a U.S. Department of Energy (DOE) Office of Science User Facility located at DOE's Argonne National...
A new research project at the TH Mittelhessen focusses on the development of a novel light weight design concept for leisure boats and yachts. Professor Stephan Marzi from the THM Institute of Mechanics and Materials collaborates with Krake Catamarane, which is a shipyard located in Apolda, Thuringia.
The project is set up in an international cooperation with Professor Anders Biel from Karlstad University in Sweden and the Swedish company Lamera from...
Superconductivity has fascinated scientists for many years since it offers the potential to revolutionize current technologies. Materials only become superconductors - meaning that electrons can travel in them with no resistance - at very low temperatures. These days, this unique zero resistance superconductivity is commonly found in a number of technologies, such as magnetic resonance imaging (MRI).
Future technologies, however, will harness the total synchrony of electronic behavior in superconductors - a property called the phase. There is currently a...
How do some neutron stars become the strongest magnets in the Universe? A German-British team of astrophysicists has found a possible answer to the question of how these so-called magnetars form. Researchers from Heidelberg, Garching, and Oxford used large computer simulations to demonstrate how the merger of two stars creates strong magnetic fields. If such stars explode in supernovae, magnetars could result.
How Do the Strongest Magnets in the Universe Form?
02.10.2019 | Event News
02.10.2019 | Event News
19.09.2019 | Event News
15.10.2019 | Materials Sciences
15.10.2019 | Interdisciplinary Research
15.10.2019 | Life Sciences