Researchers identify key protein involved in developing Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder that causes a gradual loss of coordination and muscle control over the face and body. PD affects around 1 in 10,000 men and 1 in 100,000 women. The Wistar Institute-led team has identified a protein that contributes to the onset of PD in this population and offers potential to diagnose tumors in advance of the first steps in the disease progression.

The protein identified is CAG4, a hydrophobic radar-antenna-like protein expressed from neurons in the brain of PD patients. CAG4 forms protein channels in a subset of neurons that contain chemical groups. These protein channels enable calcium signaling in the cell. When calcium signaling is activated, cellular levels of Ca2+ increase, impairing the control of Ca2+ level in the cell. This can lead to a decrease in Ca2+ concentration in the Ca2+-depleted cells. CAG4 forms channels that promote Ca2+ entry of Ca2+-mediated Ca2+ channel into phospholipids-rich Ca2+-loaded RENES (Receptor Epithelial ETC) complexes. These complexes are at the root of PD. Because of Ca2+-dependent membrane changes in RENES complexes, the formation of plaque-like protein aggregates was first observed. Consistent with this notion, PD-associated amphithelial deposits were found at sites of proteinaceous lesions in PD patients, indicating that dehydration-induced changes in proteinaceous morphology contribute to the onset of PD in PD patients.

The Wistar-led team saw a reduction in Ca2+ levels in Alzheimer’s disease brain areas, an effect that was more pronounced in patients with Parkinson’s disease than in Alzheimer’s patients. Thresholds for Parkinson’s and Alzheimer’s disease were assessed in the brain by intra-neuronal recordings of Ca2+ in the MAPK Ca2+ efflux test and in brain by market electrodes implanted in the dorsol barrel of the dorsiflex, a region at which Parkinson’s is associated with signs of PD. Both of these have been validated in the single alpha-synuclein PET imaging experiment used in this study.

“Our work provides the first insight into the cellular and molecular mechanisms underlying PD in the brain,” said senior author Christoffer Jasin, Ph.D., of the Wyss Institute for Biomedical Research, and Boston Children’s Research Institute. “Our research opens the door for new pathophysiological models for detecting the onset of PD, before the first symptoms are apparent.”

The study, published in Wiley Metabolism on November 3, 2019, was funded by the ALS Association, GSK, Janssen Research & Development, Maytag Pharma Co., Ltd., and National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, and National Cancer Institute (NIH), and included first author Rebecca Cross, Ph.D..