Managing misfolded proteins to prevent Parkinson’s disease

Scientists are getting closer to understanding one of the key processes that may drive Parkinson’s disease, and researchers at Yale are investigating whether it could eventually be slowed or even stopped. The focus is a protein called alpha synuclein. This protein is normally found in brain cells and plays an important role in how nerve cells communicate. But in Parkinson’s, some alpha synuclein can change its shape and become misfolded. These abnormal proteins can stick together and form clumps inside brain cells. These clumps, known as Lewy bodies, are one of the main features of Parkinson’s disease. Researchers have increasingly found evidence that the problem may not stay inside one brain cell. Misfolded alpha synuclein can move out of one cell and enter another. Once inside a new cell, it may cause more alpha synuclein to misfold and clump together. This creates a possible chain reaction, allowing the abnormal protein to spread through parts of the brain and damage more nerve cells. The Yale researchers are now asking an important question: can we stop this process before it reaches more cells? They studied thousands of proteins found on the surface of nerve cells to identify which ones help misfolded alpha synuclein enter the cells. They identified two proteins, called mGluR4 and NPDC1, that appear to play an important role in this process. Both are found in dopamine producing nerve cells, which are particularly vulnerable in Parkinson’s. In experiments in mice, removing either of these proteins prevented the usual loss of dopamine producing nerve cells after exposure to misfolded alpha synuclein. This suggests that blocking these pathways might make it harder for the abnormal protein to enter vulnerable brain cells. But this is still early research. The findings do not mean that these proteins can currently be targeted as a treatment for people with Parkinson’s. Much more research is needed to understand whether this approach would be safe and effective in humans. The researchers are also looking at another possible way to tackle the problem: helping the brain get rid of misfolded alpha synuclein. The brain has a drainage system that helps remove waste and unwanted material. Scientists are investigating whether improving this natural drainage could help clear alpha synuclein from the spaces between brain cells before it has a chance to enter healthy nerve cells. The two approaches could potentially work together: prevent misfolded alpha synuclein from getting into vulnerable nerve cells while also helping the brain remove the protein that is already outside them. This is important because most current Parkinson’s treatments are designed to control symptoms such as tremor, stiffness and movement problems. They can make a significant difference to daily life, but they do not stop the underlying disease from progressing. Researchers are therefore looking for ways to intervene earlier in the disease process. Instead of simply managing what happens after brain cells have been damaged, the goal is to understand what causes the damage in the first place and find ways to interrupt it. The Yale research is still at an early stage, and it is far too soon to say that a treatment or prevention strategy has been found. However, it adds to growing evidence that misfolded alpha synuclein may be an important part of how Parkinson’s disease develops and spreads through the brain. The long term hope is that if scientists can understand how these abnormal proteins move, enter nerve cells and are cleared away, they may eventually be able to develop treatments that interfere with the process. That could lead to a very different kind of Parkinson’s treatment, one aimed not only at controlling symptoms but at slowing the progression of the disease itself.