Ceramides May Be the Missing Link Between PLA2G6 Mutations and Parkinson’s, Study Suggests

Baylor College of Medicine and Texas Children’s Hospital researchers have found that a family of fat molecules, called ceramides, are key players in the development of an early onset form of Parkinson’s disease called Parkinsonism.

The study, “Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain,” was published in Cell Metabolism.

It is still unclear what exactly causes Parkinson’s disease; however, several genetic and environmental factors have been identified.

Mutations in the PLA2G6 gene have been linked to early-onset Parkinson-like disorders, including infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (aNAD), and PLA2G6-related dystonia-parkinsonism.

These disorders have different presentations and course patterns. Still, they share some features, which suggests common underlying mechanisms.

“The PLA2G6 gene encodes a phospholipase, an enzyme that modifies a type of fats called phospholipids. Phospholipids are major building blocks of our nervous system, but they have not been well characterized,” Guang Lin, PhD, postdoctoral associate in molecular and human genetics at Baylor and first author of the study, said in a press release. “We thought that we ought to investigate what this phospholipase was doing in these diseases.”

The team engineered fruit flies to specifically lack a functional iPLA2-VIA — the fly’s gene version of the human PLA2G6.

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Flies without this gene had a reduced lifespan, surviving for only about one third of the time of normal flies, along with impaired nerve cell activity and cell death.

Specifically, the team looked at the effects of the mutation on two measurements: bang sensitivity (response to mechanical stress) and the workings of the visual system.

While normal fruit flies recovered immediately from impact, flies lacking iPLA2-VIA gene took longer to recover and were paralyzed for some time after impact, indicating problems with their nervous system.

These flies also had progressive loss of electrical responses in a set of nerve cells that sense light (called photoreceptors) in the eyes.

“Confirming previous results by other researchers, we also observed that fruit flies without the iPLA2-VIA gene were healthy when they were young and presented with age-dependent neurodegeneration,” Lin said.

Looking at nerve cells under the microscope, researchers observed that flies without the iPLA2-VIA gene had abnormal lump-like structures in the cellular membranes of their photoreceptors.

The cellular membrane is mainly composed of phospholipids, small lipid molecules that separate the interior of cells from the outside environment and protect the cell from its surroundings.

Because the iPLA2-VIA gene gives origin to a phospholipase, researchers hypothesized the lumps could be due to an impaired metabolism of the phospholipids present in the cell membrane.

Surprisingly, phospholipidic content in nerve cells lacking the iPLA2-VIA gene was normal. However, ceramide levels were increased.

Chemically inhibiting ceramide in these animals partially reversed the neurodegeneration triggered by iPLA2-VIA loss, while improving nerve cell response and activity and reducing cellular stress.

Importantly, high levels of alpha-synuclein — a hallmark of Parkinson’s disease — triggered ceramide accumulation, which also was reduced upon treatment with ceramide chemical inhibitors.

This accumulation was due to a decreased capacity to recycle cellular materials using a complex of proteins known as the retromer.

“We think that our work is important because it points to a potential mechanism leading to Parkinsonism and perhaps Parkinson’s disease,” said Hugo Bellen, DVM, PhD, professor at Baylor College of Medicine, investigator at the Howard Hughes Medical Institute, and senior author of the study.

In light of these results, researchers hypothesize that accumulated ceramides are redistributed to the cell membrane, including to membranes of organelles such as mitochondria.

This gradual disruptive event will progressively create more stress, as well as mitochondrial dysfunction, “that eventually would lead to Parkinsonism and Parkinson’s disease in the long term,” Bellen said.

These findings may open new therapeutic avenues to fight Parkinson’s disease.