Scientists discover key enzyme that can protect your brain from Parkinson’s

Scientists discovered a key molecular switch to keep neurons healthy by controlling the disassembly and assembly of their energy-generating powerhouses, the mitochondria. The study illustrates how a protein complex, PP2A-B55α, acts as a clean-up crew and a controller—choosing to recycle defective mitochondria or build new ones.

This new knowledge can develop therapies for neurodegenerative disease like Parkinson's, where dysfunctional mitochondrial maintenance results in the death of neurons.

Mitochondria are the cell's power plants that generate the energy the cell needs to survive. But, like all machinery, they deteriorate over time. To stay healthy, cells must discard aging, defective mitochondria by a process known as mitophagy and replace them with shiny new ones via mitochondrial biogenesis.

When this fails—either because of excessive damage or excessive faulty mitochondria—cells begin to fail. This dysfunction is at the root of disease states ranging from Parkinson's disease to super-orphan mitochondrial diseases affecting muscle, eyes, and brain.

Until now, researchers knew that proteins like Parkin and PINK1 are responsible for tagging faulty mitochondria for degradation. They did not know, however, how the cell is capable of sensing when to activate repairing. New research conducted by Valentina Cianfanelli at Roma Tre University and Francesco Cecconi of Università Cattolica del Sacro Cuore in Rome names PP2A-B55α as the link between these two mutual occurrences.

Using human cell cultures and fruit fly models, researchers found that PP2A-B55α is an enzyme that regulates mitochondrial turnover even under non-stressed, normal conditions. In human neuron-like cells, it is responsible for "basal mitophagy," the normal recycling that keeps energy in equilibrium. That is, PP2A-B55α is not active only in cellular stress—it works behind the scenes to regulate ratios of mitochondria to a neuron's energy needs.

Cianfanelli’s team also discovered that the enzyme interacts with the Parkin-PARIS-PGC-1α pathway, which controls the production of new mitochondria. Normally, a protein called PARIS blocks mitochondrial creation by suppressing PGC-1α, the main driver of biogenesis. When cells need more mitochondria, Parkin tags PARIS for destruction, allowing PGC-1α to restart production. PP2A-B55α plays a key role in this process by modifying PARIS through phosphorylation, effectively determining whether it’s ready for Parkin to remove it.

When PP2A-B55α was low in the gene-mutated fruit flies in the PINK1 gene—a potent inducer of Parkin—their mitochondrial abnormalities and motor impairments were corrected. The flies ascended more quickly, and their mitochondria once more had a typical appearance. But this repair did not occur when Parkin was lacking, therefore confirming that PP2A-B55α acts through the Parkin-dependent pathway.

Decreasing the levels of B55α was seen to make the mitochondria healthier by causing new development of new mitochondria, and not by increasing mitophagy. Unusually, decreasing a second protein, PARIS, had similar results—increasing the development of mitochondria without affecting recycling. This suggests that PP2A-B55α is a molecular switch that allows neurons to have exactly the right number of mitochondria.

B55, he said on the other hand, promotes the elimination of defective mitochondria through mitophagy. It suppresses excessive generation of new organelles on the other, maintaining the assembly-disassembly process under control. The dual-tier regulation prevents neurons from wasting energy producing unnecessary mitochondria or putting themselves at risk by not producing enough of them.

In Parkinson's disease, mitochondrial loss is a mechanism of death in dopamine-producing neurons that contribute to the disease's movement deficit. The study's findings suggest that it is possible to restore mitochondrial equilibrium and rescue these neurons by inhibiting PP2A-B55α.

In animal models of Parkinson's disease, inhibiting B55α activity enhanced motor impairment and reversed mitochondrial dysfunction, providing the potential for therapies that could prevent or even reverse neurodegeneration.

Apart from Parkinson's, the discovery could have implications for a wide range of mitochondrial disease. Because failure of mitochondria also underlies muscle disease and even cancer, control of B55α activity can stabilize energy production in huge numbers of tissue.

Cecconi described his lab as trying to identify small molecules that will selectively cause change in B55α activity in the brain and thus come up with a "universal" drug that will correct mitochondrial balance across diverse diseases.

The study used an experimental design on a large scale involving animal and human models to confirm PP2A-B55α's function. Cells of human-like neurons were cultured and induced to decrease the amounts of B55α, and fruit fly models helped to show the behavioral effects of such change in molecules.

With advanced biochemical techniques, researchers tracked how protein levels and interaction responded when B55α was removed. This exact mapping revealed a delicate yet coordinated network that allows the unobstructed functioning of mitochondria.

Interestingly, researchers also speculate that the molecular toggle has a contribution towards exercise-induced mitophagy—a physiological process in which exercise revives mitochondria. Since exercise has been found to activate mitochondrial function, PP2A-B55α can be included in the feedback mechanism that maintains energy production homeostasis with exercise and stress adaptation.

This research can be the basis for new therapies that protect neurons and improve mitochondrial function in aging and disease. By controlling PP2A-B55α, scientists will someday fix mitochondrial dysregulation in Parkinson's, muscular dystrophies, and other illnesses based on cellular energy collapse.

The discovery also offers hints on how your everyday activities, including exercise, might influence molecular processes that keep your muscle and brain healthy.

This insight into how this enzyme functions might form the foundation of treatments that restore energy balance to cells—enabling individuals to lead healthier, longer lives with fewer opportunities for neurodegeneration.

Research findings are available online in the journal Science Advances.

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