Stressed endoplasmic reticulum, not defective mitochondria, may be culprit in Parkinson's disease neurodegeneration

Instead of causing the neurodegeneration associated with some early-onset forms of Parkinson’s disease, defective mitochondria may instead activate stress in the neighboring endoplasmic reticulum (ER), which may be neurotoxic and potentially cause this neurodegeneration, according to a study published in the journal Cell Death and Disease (2016;7:e2271). Reducing ER stress may, therefore, be neuroprotective, researchers found.

“This research challenges the currently held belief that Parkinson’s disease is a result of malfunctioning mitochondria. By identifying and preventing ER stress in a model of the disease, it was possible for us to prevent neurodegeneration. Lab experiments, like this, allow us to see what effect ER stress has on Parkinson’s disease. While the finding so far only applies to fruit flies, we believe further research could find that a similar intervention in people might help treat certain forms of Parkinson’s,” said lead researcher Miguel Martins, MD, of the MRC Toxicology Unit, University of Leicester, Leicester, England.

For their study, Dr. Martins and colleagues used a fruit fly model, accepted as a good genetic model for humans. They studied fruit flies with mutant forms of the PTEN-induced kinase 1 (pink1) or parkin genes, which are known to prevent defective mitochondrial disposal, and thus deplete energy in neurons. In humans, these same genes can be mutated and result in hereditary forms of Parkinson’s disease.

Flies with either mutation moved slower and had weakened muscles, difficulty flying, and lost dopaminergic neurons, found Dr. Martins and fellow researchers. When they compared them with normal fruit flies, flies with these mutations had increased ER stress, were slower to create proteins, and had elevated levels of binding immunoglobulin protein (BiP), a protein-folding molecule that signals stress.

Mitofusin is a protein that tethers the ER to mitochondria, and pink1 and parkin genes help to degrade this. Researchers found that the mutant flies had excess amounts of mitofusin, with more mitochrondrial attachment to their ER compared with normal flies. Thus, they suggested that ER stress may be related to additional tethering of mitochondria, which prevents removal of the defective versions.

When they lowered levels of mitofusin in these mutant flies, Dr. Martins and colleagues found that the number of tethers decreased, and the number of neurons increased. Muscles also stayed healthy, despite the defective mitochondria. Thus, they concluded, the neurodegenerative effects of Parkinson’s disease may be caused by ER stress, and not mitochondrial failure. This neurodegeneration was prevented by reducing mitofusin levels, and with chemicals specifically designed to block the deleterious effects of ER stress.