Researchers have discovered an imbalance in the amounts of fatty molecules called lipids inside the brain cells of people with Parkinson’s disease. A buildup of lipids in nerve cells may cause inflammation.
Parkinson’s disease is a movement disorder that gets progressively worse over time.
The death of dopamine-producing nerve cells in the substantia nigra region of the brain causes the illness. Dopamine is a neurotransmitter that plays several vital roles, including regulating motivation, reward, and movement.
However, the exact train of events leading to the death of dopamine-producing cells remains unclear.
Researchers have focused much of their attention on a misfolded form of a protein called alpha-synuclein as the trigger for Parkinson’s. Studies have found toxic clumps or aggregates of the misfolded protein in the brains of people with the disease.
However, an alternative theory proposes that lipid dysregulation and inflammation play a more important role, similar to the part played by fatty plaques and inflammation in the walls of arteries in cardiovascular disease.
Researchers at the Neuroregeneration Institute at McLean Hospital in Belmont, MA, have now discovered an accumulation of lipids in dopamine-producing neurons in the postmortem brains of people who had Parkinson’s.
The excess amounts of lipid in these nerve cells correlate with changes in lipid levels in neighboring cells called microglia and astrocytes. They also found evidence of inflammation.
When the researchers simulated a breakdown of lipid metabolism in an animal model of the disease, they saw remarkably similar changes.
“These results support our lipid-inflammation hypothesis in the causation of Parkinson’s disease initiation and progression,” says senior author Dr. Ole Isacson, who is the founding director of the Neuroregeneration Institute and a professor of neurology at Harvard Medical School in Boston, MA.
“[The results] may help us discover and develop new therapies by leaving behind conventional thinking about [Parkinson’s disease] pathology, which to some extent has been limited to neurons and protein aggregates,” he adds.
The study appears in the journal Proceedings of the National Academy of Sciences.
Postmortem tissue samples
The scientists compared postmortem brain tissue from 26 individuals with Parkinson’s with 23 age-matched controls without the disease.
They used fluorescent lipid-binding molecules to determine lipid levels in different brain cells in the substantia nigra.
In brain tissue from people with Parkinson’s, there was an accumulation of lipids inside dopamine nerve cells, which was matched by a deficiency of lipids within astrocytes in the same samples.
Astrocytes are star-shaped cells that support nerve cells, both structurally and through the exchange of nutrients and their byproducts.
In their paper, the researchers note that nerve cells have a limited capacity to use lipids for energy, with excess amounts being transported to neighboring astrocytes to avoid the buildup of toxic byproducts.
This did not seem to be happening correctly in the brains of individuals with Parkinson’s.
Compared with healthy brain tissue, the scientists also found excess amounts of lipid inside microglia, which are the brain’s immune cells.
They also discovered high levels of a signaling molecule called GPNMB. Scientists know that astrocytes produce this molecule in response to inflammation caused by the build up of lipids.
The scientists found that levels of this molecule correlated with the total amount of lipid in the brain tissue of individuals with Parkinson’s.
Mouse model of Parkinson’s
Finally, the scientists investigated whether they could reproduce these effects in mice by disrupting lipid metabolism in the animals’ brains.
One of the most significant genetic risk factors for Parkinson’s is a mutation in a gene for an enzyme that breaks down lipids.
When the researchers injected the mice with a chemical that inhibits this enzyme, they found the same pattern of changes in lipid distribution that they had seen in brain tissue from people with Parkinson’s.
Previous research has found telltale deposits of alpha-synuclein in mice injected with this enzyme inhibitor.
In their paper, the scientists conclude:
“Therapies and agents that reverse the pathological cell-type-specific lipid distribution in the [substantia nigra of people with Parkinson’s] could serve to prevent and reduce the progression of [Parkinson’s disease] and related neurodegenerative disorders.”
However, researchers need to carry out much more research to confirm the findings and translate them into effective and safe treatments.