In patients with Parkinson’s disease, dopamine-producing neurons and microglia cells — the “immune cells” of the brain — accumulate fatty molecules that may promote inflammation and disease progression, a new study has found.
The findings, according to researchers, suggest that therapies capable of restoring the balance of fatty molecules between brain cells could lessen disease progression.
The research was reported in the study “Cell type-specific lipid storage changes in Parkinson’s disease patient brains are recapitulated by experimental glycolipid disturbance” published in the journal PNAS.
In order to function properly, neurons and glial cells — non-neuronal cells that provide support, protection, and nutrition to neurons — need to tightly control the amount and distribution of fatty molecules, known as lipids.
A continuous exchange of lipids — often through lipid transport mechanisms — helps maintain a complex distribution of fatty molecules that is key for the brain’s physiological function.
Recent preclinical and clinical research has suggested that lipid storage and trafficking are implicated in the development of Parkinson’s. Dysfunctional lysosomal hydrolases, enzymes that can break down molecules similar to lipids, are known to increase the risk of Parkinson’s, and to lead to brain disease similar to most sporadic and genetic cases of Parkinson’s.
Yet, few studies have addressed how lipids are distributed in the brains of patients with the disease.
Now, researchers from the Neuroregeneration Institute at McLean Hospital, in Massachusetts, reported the findings of a study that sought to assess and compare the content and distribution of lipids in different brain cells, both in patients with Parkinson’s those of healthy people used as controls.
Specifically, they performed post-mortem tissue analyses using samples obtained from patients and age-matched healthy individuals from a brain region called the substantia nigra, which is involved in controlling voluntary movements and often is affected in people with Parkinson’s.
The team started by analyzing the neutral lipid content — looking at the levels of two types of lipids called triglycerides (TG) and diglycerides — in the overall substantia nigra, but didn’t find any differences between patient and control samples.
However, they noticed TG levels were correlated with those of glycoprotein non-metastatic melanoma protein B (GPNMB) in patient samples. GPNMB is a stress immune response molecule involved in inflammatory signals that are associated with lipid accumulation.
Next, researchers looked at cell type specific changes in lipid distribution. Using a fluorescent dye that labels lipids, called BODIPY, and markers to detect different cell types, they found the lipid content of dopaminergic neurons in patient samples was significantly increased — by nearly twofold — when compared to controls.
In addition, they found the number of astrocytes, a group of star-shaped glial cells that provide nourishment to neurons, was six times higher in the substantia nigra of patients with Parkinson’s compared with controls. Yet, the content of neutral lipids in these cells was three times lower in patient samples.
Moreover, they observed that astrocytes’ lipid content was inversely correlated with the lipid levels found in neighboring dopamine-producing neurons.
Neutral lipids also were found to accumulate in microglia cells, which are considered the immune cells of the central nervous system (composed of the brain and spinal cord). They also found the substantia nigra of patients with Parkinson’s contained more, and larger, microglia cells, and had higher levels of BODIPY staining compared with control brain samples.
“Our study emphasizes the importance of cooperative use, storage, and transport of lipids between brain cell types in Parkinson’s disease. Mechanisms involved in balancing cellular lipids — especially neutral lipids — such as we have characterized here, have been relatively understudied in the neurodegenerative diseases,” Oeystein R. Brekk, PhD, an assistant neuroscientist at the Neuroregeneration Institute and the study’s first author, said in a press release.
To understand which mechanism was behind this altered lipid distribution in patient samples, researchers used a mouse model of Parkinson’s in whicy the activity of the lysosomal enzyme glucocerebrosidase was inhibited by conduritol beta epoxide (CBE).
Glucocerebrosidase is responsible for breaking down a fatty substance called glucocerebroside inside lysosomes and, when impaired, leads to the accumulation of alpha-synuclein. Aggregates of alpha-synuclein are toxic to brain cells and are one of the hallmarks of Parkinson’s. Lysosomes are small cell compartments that digest and recycle different types of molecules
In this model, researchers found that dopaminergic neurons and microglia cells had a higher lipid content, similar to what they had seen in patient samples. A lower lipid level also was found in astrocytes, meaning that blocking the activity of glucocerebrosidase was sufficient to recapitulate the distribution of fatty molecules observed in patient brain samples.
“Remarkably, we can model these new findings in Parkinson’s disease versus healthy aging, microglia and astrocyte interactions in the vulnerable brain regions, precisely by mechanisms that block a lysosomal lipid breakdown pathway, shown to be a strong risk factor for developing [Parkinson’s],” said Ole Isacson, MD, founding director of the Neuroregeneration Institute at McLean Hospital and the study’s senior author.
“These results support our lipid-inflammation hypothesis in the causation of Parkinson’s disease initiation and progression and may help us discover and develop new therapies by leaving behind conventional thinking about [Parkinson’s disease mechanisms], which to some extent has been limited to neurons and protein aggregates,” Isacson said.
“Based on these findings, it is reasonable to propose that restoring lipid homeostasis [balance] between neurons, astrocytes, and microglia could potentially influence [Parkinson’s disease mechanisms] and disease progression,” the researchers concluded in the study.
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