Toxic clumping of the protein alpha-synuclein, a hallmark of Parkinson’s disease, can lead to a calcium imbalance in which the mineral builds up to harmful levels in neurons, according to a study in mouse and human cells. at the beginning of the evolution of the neurodegenerative disease. .
Unique alpha-synuclein molecules activate a calcium pump in the cell membrane. A calcium pump is a protein that moves calcium ions out of cells to keep calcium levels within a healthy range.
However, when alpha-synuclein began to clump together, this activation shifted to another calcium pump located inside the cells, disrupting the calcium balance. This change is thought to occur early in the course of Parkinson’s disease and could be a tipping point in the development and progression of the disease, according to the researchers.
The discovery is an important step toward understanding the mechanisms behind Parkinson’s disease, the scientists noted, adding that tackling calcium balance could offer new ways to diagnose and treat the disease.
The study, “Monomeric α-synuclein activates the plasma membrane calcium pump”, was published in EMBO magazine.
The calcium pump in cells, when activated, prevents imbalance
In Parkinson’s disease, single units of alpha-synuclein can become incorrectly shaped and clump together into toxic clumps that damage neurons, contributing to the development and progression of the disease over time. However, the function of these free individual units remains unclear.
Using alpha-synuclein as a bait to catch and attract any interacting proteins, an international team led by researchers from the Danish Translational Neuroscience Research Institute at Aarhus University (DANDRITE), Denmark, discovered that free alpha-synuclein activates a calcium pump, called PCMA, in the cell membrane, preventing calcium buildup.
Calcium ions can move in and out of neurons, and their flow can control the amount of molecular messages sent by neurons to neighboring cells. In neurons obtained from mouse brains, free alpha-synuclein is mapped to PMCA at the synapse, the place of close contact between nerve cells where they release signals to communicate with each other.
Further experiments showed that free alpha-synuclein activated PMCA, as evidenced by a significant increase in calcium flux out of neurons.
“Activation appears to be of particular importance in the presynaptic area of neurons, responsible for transmitting signals in the brain’s neuronal network,” said Poul Nissen, PhD, lead author of the study at Aarhus University. , in a university press release.
“It is known that aSN (alpha-synuclein) accumulates in the presynaptic compartment, and our study shows, for the first time, that aSN and PMCA appear together in this area. Furthermore, we show that aSN stimulates calcium excretion by neurons,” Nissen added.
This new function of (alpha-synuclein) is relevant for the calcium homeostasis (balance) of neurons.
Unlike calmodulin – until now the only known activator of PMCA – single molecules of alpha-synuclein activated the calcium pump in the presence of negatively charged fatty molecules or those with a negative electrical charge. This suggests that alpha-synuclein may complement calmodulin, which acts in neutral or positively charged environments.
“This novel function of aSN is relevant to calcium homeostasis (balance) of neurons and specifically presynaptic compartments, where PMCA plays a key role in calcium homeostasis,” the researchers wrote.
Although early, the results open the door to possible diagnostic and treatment strategies
Abnormal calcium flux has been associated with the early formation of toxic clumps of alpha-synuclein in neurons of Parkinson’s patients with mutations in SNCA embarrassed. This gene provides instructions for making alpha-synuclein.
“Our lab has previously shown that the early clumped stages of aSN activate another calcium pump, SERCA, which is found in an internal organelle (structure) of the cell” called the endoplasmic reticulum, said Poul Henning Jensen, MD, PhD, another researcher on the study. Aarhus.
Building on this information, the researchers further observed that while SERCA was indeed activated by small clusters or aggregates of alpha-synuclein, it was not activated as much by single units of the protein. The opposite was true for PMCA.
In addition, an alpha-synuclein protein from A30P — a SNCA Parkinson’s disease-related mutation that causes the protein to clump together at a much faster rate – did not activate PMCA as much as normal protein in the presence of negatively charged fatty molecules.
This suggests that when alpha-synuclein begins to clump, activation shifts from PMCA to SERCA, which returns calcium ions to the endoplasmic reticulum, thereby increasing calcium levels in neurons.
A mathematical model revealed that PMCA activation is likely key to calcium balance, when neurons emit repeated signals and calcium ions constantly flow into them. Free alpha-synuclein would prevent calcium accumulation which could be toxic to neurons.
It is possible that early manifestations of Parkinson’s disease result from a disturbance in calcium balance due to alpha-synuclein clumping or mutations, such as A30P, that alter the ability of the protein to bind to fatty molecules.
Although future studies are needed to further explore the link between alpha-synuclein and calcium balance, these findings open the door to potential diagnostic and treatment strategies aimed at addressing early calcium changes in AD. Parkinson’s and other neurodegenerative diseases, according to researchers.