Brain cells that are usually destroyed in Parkinson’s disease have been rescued in a rat model of the disease. Easing the movement of proteins within key neurons reversed the effects of Parkinson’s on the cells. The approach might one day work in humans as a way of treating the debilitating neurological disorder.

Parkinson’s disease is characterised by rigid, slow movement or other problems with body coordination. One of the hallmarks of Parkinson’s is the demise of brain cells that produce the chemical dopamine, which transmits signals between brain cells.

Current treatments for Parkinson’s aim to boost levels of dopamine in patients’ brains. But giving people dopamine precursor chemicals to this end can create further problems by causing their natural production of dopamine to decline even further.

Better treatments could be possible if we knew what makes dopamine-producing cells die in the first place. Previous work has suggested that an overabundance of a protein called alpha-synuclein may be to blame. Now a new study provides clues as to how alpha-synuclein might wreak havoc inside dopamine-producing cells.


Ferrying proteins

Susan Lindquist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and colleagues began by confirming that if yeast cells were engineered to vastly overproduce alpha-synuclein, they died. They then randomly screened 3000 genes – about half the total number of genes in yeast – to see which ones influenced the toxicity of the protein.

This test pointed to genes involved in an important biological pathway for proteins within cells. Proteins are folded in a part of the cell known as the endoplasmic reticulum and then transported to another part called the Golgi apparatus, which packages and ships them off to their final destination. Alpha-synuclein seemed to somehow prevent a molecule called Ypt1p from doing its job of ferrying proteins between these two sites.

So the team tried boosting Ypt1p in the engineered yeast cells and found that this protected them. The cells survived even with high levels of alpha-synuclein present.

Dopamine-producing neurons are more prone to being killed by excess alpha-synuclein than other cells because dopamine accumulates in the cell when the transport system is derailed, the researchers speculate. And because dopamine is a highly chemically reactive molecule it kills its cell.

Fly and rat cells

Lindquist and colleagues tested their approach of fixing the damaged transport system by applying it to dopamine-producing fly and rat cells that had been engineered to produce too much alpha-synuclein. In flies they managed to fully rescue the loss of cells.

In rat neurons, inserting a gene for a molecule called Rab1 – the equivalent of Ypt1p –saved more than 50% of the cells from death.

“Given the wide spectrum of defects in cells accumulating defective proteins, it is surprising to see that fixing only one of the defects shows such a significant improvement,” says Seung-Jae Lee of Konkuk University in Seoul, South Korea.

Researchers suggest a drug that boosts levels of the human equivalent of Rab1 may reverse the loss of dopamine-producing cells in Parkinson’s patients. But they caution that prospect is still a distant one, and other biological pathways may prove more worthwhile targets.

“Putting all our eggs in one basket at this stage would be a huge mistake,” says Lindquist.

Lee says: “It remains to be addressed whether this approach would be able to reverse the course of ongoing neurodegeneration.” Even when people are diagnosed with Parkinson’s at the earliest stage of the disease, it is assumed that they have suffered brain damage.

Journal reference: Science (DOI: 10.1126/science.1129462)