Fatty molecule may mark treatment efficacy with common mutations

Urine levels of molecule high with LRRK2, GBA1 mutations in patients, carriers

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Levels of a fatty molecule called Bis(monacylglycerol) phosphate, or BMP, are significantly elevated in the urine of people with certain LRRK2 and GBA1 mutations linked to Parkinson’s disease, a new study suggests.

Measuring urinary BMP levels could be a useful way of gauging the effectiveness of potential treatments that target these disease-linked mutations, the researchers noted.

The study, “LRRK2 and GBA1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts,” was published in npj Parkinson’s Disease

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BMP levels 3 to 7 times higher in urine of people with LRRK2 mutations

Certain genetic mutations are known to increase the risk of Parkinson’s disease, with those in the LRRK2 and GBA1 genes showing the strongest associations. While the mechanisms behind these links are not completely understood, both genes are important for the functioning of the lysosome.

The lysosome is a cellular compartment that acts like a molecular recycling center, breaking complex molecules down into simple components that can be repurposed by the cell.

A team led by scientists in the U.S. conducted an analysis into how BMP levels, measured in the urine, associate with Parkinson’s-linked genetic mutations. BMP, a fatty molecule, is known to both regulate and be affected by lysosomal function.

They used data from the Parkinson’s Progression Markers Initiative (PPMI), a large international study following patients and healthy people over time.

A total of 149 Parkinson’s patients with LRRK2 mutations, 76 patients with GBA1 mutations, 379 people without known disease-related mutations (sporadic Parkinson’s), and 190 healthy adults, as controls, were included in the study.

Additional groups of Parkinson’s carriers, people harboring a related genetic mutation but without the disease, also were analyzed: 197 carriers with LRRK2 mutations and 178 with GBA1 mutations.

BMP levels in the urine were similar between sporadic Parkinson’s patients and controls.

In turn, urinary BMP levels were significantly higher, between three to seven times, in people carrying LRRK2 mutations, regardless of whether they had Parkinson’s or were carriers, compared with sporadic Parkinson’s patients and healthy controls.

Similarly elevated levels were found in carriers of each of the two LRRK2 mutations included in the analysis, G2019S and R1441G.

People harboring a specific GBA1 mutation called N409S also had significantly higher urinary BMP levels relative to the sporadic Parkinson’s and control groups. However, the magnitude of this increase was “much smaller,” the researchers wrote — only about 40% higher. Other mutations in the GBA1 gene were not associated with altered urinary BMP levels.

These findings suggest that measuring BMP could help identify people with Parkinson’s-associated mutations, but would not be useful for detecting Parkinson’s itself since levels are also elevated in mutation carriers without the disease.

As such, “urine BMP is a trait, but not a state, marker” of Parkinson’s, the researchers wrote.

They also noted that the altered urinary BMP levels seen in people harboring LRRK2 or GBA1 mutations add to the growing body of research that suggests these genes play important roles in lysosome function.

No links evident between BMP levels and disease progression

Researchers conducted a series of statistical tests to see if urinary BMP levels at the study’s start (baseline) could predict disease progression over five years in terms of Parkinson’s-typical brain damage, symptom severity, and cognitive problems.

No significant associations existed between BMP levels and these clinical and imaging measures in any of the patient groups, results showed.

“We were not able to see the prognostic utility of baseline BMP on [Parkinson’s] progression … precluding its use for patient enrichment or monitoring disease progression,” the researchers wrote.

However, “it is noteworthy that the LRRK2 and GBA1 genetic [groups] in PPMI show the minimal progression on these clinical and [imaging] outcomes over 5 years since enrollment” in this international study, they added.

When looking at LRRK2 mutation carriers, the researchers also found that urinary BMP levels remained generally stable over two years.

Given the potential link between this fatty molecule and the function of Parkinson’s-linked genes, the scientists speculated that urinary BMP levels might be useful as a marker to assess the effectiveness of therapies specifically targeting these disease-linked mutations.