Fatty molecule may cause nerve cell damage in Gaucher: Study

Findings also shed light on mechanisms linking disease to Parkinson's risk

Marisa Wexler MS avatar

by Marisa Wexler MS |

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In Gaucher disease, the toxic buildup of a fatty molecule called glucosylsphingosine (lyso-Gb1) leads to issues with how nerve cells generate energy and other cellular problems, according to a new study. Lyso-Gb1 is a biomarker of disease burden and response to treatment.

The findings help to understand how the accumulation of fatty molecules contributes to neurological symptoms in Gaucher disease, and they also shed light on the mechanisms linking Gaucher to a higher risk of Parkinson’s disease.

The study, “Glucosylsphingosine affects mitochondrial function in a neuronal cell model,” was published in Communications Biology.

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Why do some Gaucher patients face Parkinson’s disease risk?

Lyso-Gb1 a well-established Gaucher biomarker

Mutations in the GBA1 gene cause Gaucher disease. This gene provides instructions for making an enzyme that breaks down certain fatty molecules, such as glucocerebroside (Gb1). Without this enzyme, these fatty molecules build up to toxic levels in cells, causing damage that ultimately drives disease symptoms.

Within cells, Gb1 can be converted into another fatty molecule called lyso-Gb1, which also builds up in people with Gaucher. Lyso-Gb1 is a well-established Gaucher biomarker, helping doctors determine the severity of the disease and how well it responds to treatments.

Along with the buildup of Gb1, increasing levels of lyso-Gb1 in cells are thought to drive damage in Gaucher disease. However, the exact mechanisms through which lyso-Gb1 damages cells are not entirely understood.

Our findings show that glycolysis can rescue reduced [energy] production rate at the low dose, but not adequately at the high dose.

To shed light on these mechanisms, scientists in the U.K. conducted a series of experiments in which they incubated nerve cells with different levels of lyso-Gb1 and then examined how the cells’ molecular activity had changed.

Results revealed that lyso-Gb1 led to dysregulation of mitochondria, which are known as the powerhouses of cells. These cellular structures are necessary for generating the energy cells need to survive and function.

In turn, an alternative mechanism that cells can use to generate energy, called glycolysis, became more active. The researchers showed that the uptick in glycolysis could compensate for the dysfunctional mitochondria at low levels of lyso-Gb1, similar to what’s seen in people with moderate Gaucher disease.

But at higher lyso-Gb1 levels, similar to those observed in people with severe Gaucher, glycolysis could not compensate for the mitochondrial dysfunction.

“Our findings show that glycolysis can rescue reduced [energy] production rate at the low dose, but not adequately at the high dose,” the researchers wrote.

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Higher levels of fatty molecule associated with type of nerve cell damage

The scientists also noted that glycolysis is useful for short-term energy generation, but is much more inefficient than making energy with mitochondria. As such, they speculated that cells relying on glycolysis for long-term energy generation might cause cellular stress and other problems that contribute to Gaucher disease.

Results also showed that higher lyso-Gb1 levels were associated with increased oxidative stress, a type of cellular damage. There were also changes in protein modifications in the presence of lyso-Gb1, particularly in proteins important for maintaining cellular structure and transport. These modifications may further compromise neuronal function.

The findings suggest that lyso-Gb1 accumulation can disrupt multiple aspects of neuronal metabolism, not just mitochondrial function. This may contribute to the neurological complications seen in Gaucher disease and possibly explain the higher risk of Parkinson’s disease in patients with GBA1 mutations.

“These cellular deficiencies … may eventually lead to damage of vulnerable cells such as neurons and potentially answer some of the questions regarding the disease mechanisms associated with [Gaucher disease] and GBA-related [Parkinson’s disease],” the team concluded.