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Researchers Identify Point-of-Entry for Toxins That Harm Brain Cells in Parkinsonís
- Nov 14 2016
In the September 30 edition of Science, researchers say they have discovered how toxic protein clumps enter brain cells in Parkinson’s disease (PD) -- by unlocking a molecular “door” called LAG3. They also showed that preventing the protein clumps (alpha-synuclein) from entering through this door could slow or prevent PD-like symptoms in mice, suggesting new strategies for therapies.
PD develops when certain brain cells – cells that normally help control the body’s movement – become sick and die. These brain cells become sick when they accumulate clumps of alpha-synuclein protein, also called Lewy bodies. Recent research suggests that this abnormal alpha-synuclein may be able to spread from cell to cell, like an infection.
For the new study, researchers led by Ted M. Dawson, M.D., Ph.D., at Johns Hopkins University, investigated how the protein clumps get inside of healthy dopamine neurons, the type of brain cells lost in PD.
The scientists began by studying cells in the laboratory. At the beginning, toxic alpha-synuclein wasn’t able to enter any of the cells. One by one, researchers made different cells with unique “locks” that could only be unlocked with the right molecular “key.” They found just one receptor, called LAG3, that opened a door into the cell and allowed alpha-synuclein in. After that, they also studied mice without the LAG3 receptor and studied additional cells to see whether antibodies could keep the cell door “locked’ and block LAG3 from letting toxic proteins in.
- Alpha-synuclein clumps bind to a receptor protein called LAG3, which allows the α-synuclein to enter a cell.
- When normal mice were injected with alpha-synuclein clumps, their dopamine neurons began to die and they developed PD-like movement symptoms. But mice that lacked LAG3 had dramatically fewer PD-like symptoms.
- Antibodies that blocked LAG3 prevented alpha-synuclein clumps from entering nerve cells cultured in a laboratory dish.
What Does It Mean?
It remains unknown why and how PD progresses. Autopsy studies show that as the disease progresses, PD-related changes in alpha-synuclein clumps spread in the brain. According to a recent theory that is gaining ground, PD may worsen when toxic clumps of alpha-synuclein protein spread from neuron to neuron. How alpha-synuclein exits dying cells is not known, but the new study helps explain how abnormal alpha-synuclein could get into healthy cells.
The researchers identified a receptor protein, LAG3, which in effect opens a door in the cell membrane, allowing alpha-synuclein to enter. They also showed that eliminating or blocking LAG3 helps prevent the spread of alpha-synuclein and delay the death of dopamine neurons. This raises the possibility that drugs targeted at LAG3 might slow the progression of PD in people. In fact, antibodies that target LAG3 already are being tested in clinical trials for use in cancer therapy. If these therapies are proven safe, and if further research bears out their potential benefit for PD, the process of testing them for PD could be hastened.
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Reference: Mao X, Ou MT, Karuppagounder SS, et al. (2016). Pathological a-Synuclein Transmission Initiated by Binding Lymphocyte-Activation Gene 3. Science DOI: 10.1126/science.aah3374
Source Date: Nov 14 2016