 Some inherited forms of early-onset Parkinson's disease have typically been blamed on poorly-functioning mitochondria, the powerhouses of cells. Without reliable sources of energy, neurons wither and die. Over time, neurodegeneration shows up in patients as trembling and difficulty walking, among other symptoms. But that might not be the whole story. Using the common fruit fly to investigate more fully, researchers have now found that the bulk of the damage stems from a related but different source. The neighboring maze-like endoplasmic reticulum. The endoplasmic reticulum, or ER, has the important job of folding proteins so that they can do the vast majority of work within cells. Misfolded proteins are dangerous and cells often treat them as garbage, halting protein production if there are too many of them. While this system is protective, it also stalls the manufacture of vital proteins, and eventually this will kill neurons. To find out if this ER stress might be at play in Parkinson's, researchers analyzed flies with mutant forms of the pink one or parkin genes. These mutations are already known to starve neurons of energy by preventing the disposal of defective mitochondria. Pink one and parkin are also mutated in humans and result in hereditary versions of the disease. Much like Parkinson's patients, flies with either mutation move more slowly and have weakened muscles. The insects struggle to fly, and they lose dopaminergic neurons in their brains, a classic feature of Parkinson's. Compared to normal flies, the scientists found that the mutants were in the throes of ER stress. The flies were not putting proteins together as quickly as their regular peers, and they had elevated levels of the protein-folding chaperone bip, a telltale sign of stress. But what triggers the ER stress? One function of pink one and parkin is to help degrade mitophusin, a protein that tethers the endoplasmic reticulum to mitochondria. Mutant flies have an abundance of this protein, so perhaps the ER stress is related to extra tethering to the defective powerhouses. Indeed, when the researchers looked at the mutants, they had more of their mitochondria attached to the ER than normal flies. These contacts are not good for brains. Mutant flies, which have more of them, have fewer dopaminergic neurons. Reducing the number of contacts, though, can prevent that loss. When scientists experimentally lowered the amount of mitophusin in the mutants, the number of contacts fell, and the neuron number jumped back up. It also kept the flies muscles healthy, even though the mitochondria themselves were still defective. The results suggest that the neurodegeneration in Parkinson's is a result of ER stress rather than a general failure of the mitochondria. In fact, the scientists were able to prevent neurodegeneration in mutant flies, not only by reducing mitophusin, but also with chemicals that block the effects of ER stress. While the finding so far only applies to fruit flies, the researchers think a similar intervention in people might help treat certain forms of Parkinson's.