A new study shows how dysfunctional packaging of the neurotransmitter dopamine triggers toxic processes in neurons – and how this can be repaired with simple delivery of energy (ATP).

Parkinson’s gradually destroys dopamine-producing neurons in a specific area of the midbrain, causing tremors, stiffness, and movement problems. Two key features are the accumulation of the protein α-synuclein into Lewy bodies and the loss of dopaminergic neurons. “Dopamine oxidizes to produce toxic substances and causes lasting damage to the neurons if it is not properly packaged in small bubbles, known as vesicles – but the cause of this dysfunctional packaging of dopamine was hitherto unclear,” says Lena Burbulla, Professor of Metabolic Biochemistry in the Faculty of Medicine at LMU and member of the SyNergy Cluster of Excellence. She is the lead author of a study that was recently published in the journal Science Advances.

Neurons from stem cells placed under the microscope

The researchers converted induced pluripotent stem cells (iPSCs) from a Parkinson’s patient with a defective DJ-1 gene and genetically modified iPSCs lacking the DJ-1 gene into neurons. “The lack of DJ-1 causes energy problems that occur in many variants of Parkinson’s,” explains Burbulla. Using high-precision protein analysis (proteomics), state-of-the-art imaging and sensitive dopamine sensors, the team of researchers revealed how dopamine is “packaged” incorrectly in the cells.

Dopamine becomes a cell toxin

The protein VMAT2, which is responsible for the secure packaging of dopamine into the vesicle, does not function properly in Parkinson’s neurons: It does not take up enough dopamine – firstly because there is a lack of energy in the form of ATP (adenosine triphosphate), the universal energy carrier in cells, and secondly because the neuron does not produce enough VMAT2. As a result, dopamine ultimately oxidizes to form toxins. Another crucial factor here is that misfolded α-synuclein protein accumulates – probably a consequence of the oxidized dopamine, which can bind proteins and promote their accumulation. As the researchers were able to show, simple delivery of ATP repaired the packaging of dopamine and stopped the damage.

Therapeutic potential of dopamine packaging

“This discovery links an energy deficiency to the packaging of dopamine and neuron vulnerability – a new mechanism for Parkinson’s,” says Burbulla. It shows that intact VMAT2 and secure packaging of dopamine are key factors for protecting midbrain neurons and preserving them could slow down the pathology. “iPSC-based disease modeling will enable future therapy tests to be conducted directly in patient cells and will accelerate translation from laboratory to clinic.”