A new study from the Medical Faculty of the Ludwig Maximilian University (LMU) in Munich shows how a disturbed packaging of the messenger substance dopamine in nerve cells triggers toxic processes in Parkinson’s disease. The researchers were also able to demonstrate that a simple supply of energy in the form of ATP (adenosine triphosphate) can repair this damage.

Parkinson’s leads to the gradual death of dopamine-producing nerve cells in the midbrain and causes typical symptoms such as tremors, muscle stiffness and movement disorders. Central pathological features are the accumulation of the protein α-synuclein in Lewy bodies and the loss of dopaminergic nerve cells. The study, which has been published in the journal Science Advances , sheds light for the first time on the cause of faulty dopamine packaging in synaptic vesicles.

Under the direction of Prof. Dr. Lena Burbulla, Professor of Metabolic Biochemistry at LMU and member of the SyNergy Cluster of Excellence, the scientists studied induced pluripotent stem cells (iPSCs) from a Parkinson’s disease patient with a mutation in the DJ-1 gene as well as genetically engineered DJ-1-deficient cells, which they converted into dopaminergic nerve cells. The lack of DJ-1 causes energy deficits that occur in many forms of Parkinson’s disease.

Using high-precision proteomics, modern imaging techniques and sensitive dopamine sensors, the researchers found that the protein VMAT2 – responsible for the transport of dopamine in vesicles – is disrupted in diseased cells. It absorbs too little dopamine because, on the one hand, ATP is lacking as a universal energy carrier and, on the other hand, too little VMAT2 is produced. As a result, free dopamine in the cytosol oxidizes into toxic substances, which damages nerve cells and promotes the accumulation of misfolded α-synuclein.

Crucially, the intake of ATP restored vesicle function, improved dopamine packaging and prevented the toxic consequences. The study links energy deficiency to faulty dopamine sequestration and neuronal vulnerability – a previously unknown mechanism in Parkinson’s pathogenesis.

The results underline that intact VMAT2 function and safe dopamine packaging are central protective mechanisms for dopaminergic midbrain nerve cells. Preserving them could slow down disease progression. Models based on the patient’s own iPSCs will enable direct therapy tests in human cells in the future and could accelerate the transfer of laboratory results to the clinic.

Original Paper:

VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1–linked Parkinson’s neurons | Science Advances

Editor: X-Press Journalistenbüro GbR

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