Energy shortage in cells may drive toxic dopamine buildup in Parkinson’s
Scientist: Discovery reveals 'a new mechanism' underlying disease symptoms
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- Researchers discovered that a cellular energy shortage in Parkinson's may be an underlying disease mechanism.
- Impairments in dopamine processing may lead to toxicity, driving disease development.
- These findings may lead to new strategies for the treatment of Parkinson's.
Impaired cellular energy may interfere with how dopamine — the key chemical messenger that is in short supply in Parkinson’s disease — is packaged and handled inside nerve cells, a new study has found.
According to the researchers, such disruptions, and a resulting energy shortage, may promote the formation of toxic dopamine byproducts and the buildup of abnormal alpha-synuclein protein, a hallmark of the disease.
“This discovery links an energy deficiency to the packaging of dopamine and neuron vulnerability – a new mechanism for Parkinson’s,” Lena Burbulla, PhD, a professor at the Faculty of Medicine at Ludwig-Maximilians-Universität München (LMU) in Germany and the study’s lead author, said in a LMU press release detailing the research findings.
The team noted that efforts toward more secure packaging for dopamine may help slow the disease’s development.
“These findings have substantial implications for future therapeutic strategies” in Parkinson’s, the researchers wrote.
The study, “VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1–linked Parkinson’s neurons,” was published in the journal Science Advances.
Parkinson’s disease is marked by the gradual loss of dopamine-producing nerve cells in the brain and the buildup of abnormal clumps of the protein alpha-synuclein. Dopamine is a chemical messenger that plays a key role in motor function.
Researchers focus on impairments in cell energy processes
Recent work has identified a harmful chain of events in Parkinson’s that begins with mitochondrial dysfunction — impairments in a cell’s energy factories — and leads to dopamine oxidation, a process that generates toxic byproducts that can damage neurons. Neurons are nerve cells in the body that play a role in processes from breathing to talking, eating, walking, and thinking.
According to Burbulla, “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.” However, “the cause of this dysfunctional packaging of dopamine was hitherto unclear,” Burbulla noted.
One protein of interest is DJ-1, which has been linked to inherited forms of Parkinson’s and appears to help protect nerve cells from this kind of stress. Scientists also suspect that defects in VMAT2, a protein that normally packages dopamine safely into tiny sacs called vesicles, may allow excess dopamine to remain in the cell, where it can become toxic.
To tackle these questions, LMU researchers turned to lab-grown human midbrain dopamine neurons made from induced pluripotent stem cells (iPSCs). The team engineered some of these cells to lack DJ-1 (knockout) and compared them with similar neurons that still had DJ-1 and served as controls.
The researchers then performed a proteomics analysis — a large-scale study of proteins — in two pairs of DJ-1 knockout and control neurons and found that the dopamine vesicle transporter VMAT2 was among the proteins whose levels were most strongly reduced in DJ-1-deficient neurons. Further analyses pointed to broader problems in pathways related to synapses and synaptic vesicles, the structures nerve cells use to store and release chemical signals.
Additional experiments showed that DJ-1 normally interacts with proteins involved in intracellular vesicles, mitochondria, and the cell’s internal scaffolding, known as the cytoskeleton. These interactions were lost in neurons lacking DJ-1, further supporting the idea that the protein is important for maintaining healthy vesicle function.
Findings could lead to new treatments for Parkinson’s
Using advanced imaging approaches, the researchers found that DJ-1-deficient neurons had fewer VMAT2-positive synapses and VMAT2-containing vesicles at individual synapses. The amount of VMAT2 per vesicle was also reduced. Together, these findings suggested that the dopamine storage machinery was impaired at multiple levels.
The team then explored a third cell model derived from a person with DJ-1-linked Parkinson’s disease and confirmed that VMAT2 levels were also reduced in this model. Functional tests showed that these neurons were less able to take up and store dopamine-like molecules inside vesicles, indicating that VMAT2 activity was impaired, not just its abundance.
Because VMAT2 depends on mitochondrial energy, the researchers next examined mitochondrial health. The team found that DJ-1-deficient neurons had more dysfunctional mitochondria and lower levels of ATP, the cell’s main energy source. This energy shortage likely contributed to VMAT2’s failure to properly package dopamine into vesicles.
“The lack of DJ-1 causes energy problems that occur in many variants of Parkinson’s,” Burbulla said.
Structural studies also revealed that synaptic vesicles in DJ-1-deficient neurons were abnormal. Compared with controls, these neurons had more unusually large vesicles and other strange tubular structures at synapses. Levels of clathrin — a protein essential for recycling vesicles after they release their contents — were about doubled, suggesting additional problems in the vesicle recycling process, the researchers found.
These defects had clear downstream or resulting consequences. DJ-1-deficient human neurons showed increased dopamine oxidation and higher levels of alpha-synuclein, including disease-linked oxidized and nitrated forms of the protein.
[This discovery may lead to] previously unknown avenues for the development of interventions tailored to dysfunctional pathways [involving dopamine].
The researchers noted that, while mouse dopamine neurons lacking DJ-1 also showed lower VMAT2 levels, they did not exhibit the same degree of dopamine oxidation. This supports the idea that important species differences may help explain why mouse models do not fully mimic human Parkinson’s disease.
Finally, the researchers tested whether restoring cellular energy could improve these abnormalities. Treating DJ-1-deficient neurons with ATP boosted VMAT2 activity, lowered clathrin levels, and reduced both dopamine oxidation and alpha-synuclein buildup.
Overall, these findings suggest that energy failure, impaired dopamine storage, and faulty vesicle recycling may work together to drive nerve cell damage in DJ-1-related Parkinson’s disease, according to the researchers.
This discovery may lead to “previously unknown avenues for the development of interventions tailored to dysfunctional pathways of vesicular DA [dopamine] sequestration,” the team concluded.
