A study by Yale scientists provides insights that could lead to new therapies for individuals with Gaucher disease (GD), while offering new understanding into the study of other diseases, including Parkinson’s. This breakthrough research in the study of forms of Gaucher disease that cause neurodegeneration (nGD) has implications for individuals with rare diseases such as Gaucher, and those with more common diseases.
Gaucher disease is a genetic disorder of metabolism, causing rare health problems in individuals with the disorder. It is caused by the inheritance of two genetic mutations in a gene, GBA1, that allow for the buildup of a fatty molecule, also known as a lipid, glucocerebroside, said Pramod K. Mistry, MBBS, PhD, professor of medicine, (digestive diseases), of pediatrics, and of cellular & molecular physiology at Yale School of Medicine (YSM). Individuals who are healthy carriers (with only one copy of the mutation) harbor the most important genetic risk factor for Parkinson’s disease, a neurodegenerative disorder that affects movement.
A research article published in eLife provides new insights into the molecular mechanisms underlying Gaucher disease. As the lipids build up to toxic levels within cells in the brain in Gaucher disease, brain immune cells, called microglia, are altered to become Damage Associated Microglia. They then attract immune cells from outside the brain to trigger a cascade of events that lead to loss of neurons. As healthy microglia decline, neuronal damage worsens. This effect can be monitored by measuring serum levels of a marker called Neurofilament Light Chain, Gaucher lipid, as well as a lipid transporting protein, apoE, Mistry explained.
Mistry and Shiny Nair, PhD, research scientist at YSM, found that lowering the level of Gaucher lipids in the brain using an inhibitor of the enzyme that forms glucosylceramide (glucosylceramide synthase), restored healthy microglia and reversed the influx of damaging immune cells that comprise macrophages and NK cells.
“Applying single-cell technology, immune profiling and lipidomics to Gaucher brains, we found early events can be monitored by newly discovered blood biomarkers of nGD before onset of noticeable neurological disease,” Mistry said.
The results of the study have major implications for devastating nGD, for which currently there are no treatments, said an Insight article accompanying the Yale paper.
“Our findings advance the understanding of nGD disease mechanisms while identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials, and illuminate therapeutic targets,” Mistry said. “Our studies in nGD build upon numerous studies from our group recently that have shown the importance of Gaucher lipids in triggering inflammation in the body in rare Gaucher disease but also in more common conditions.”
Read the eLife article, Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy at https://doi.org/10.7554/eLife.79830.
Since forming one of the nation’s first sections of hepatology and then gastroenterology over 50 years ago, Yale’s Section of Digestive Diseases has had an enduring impact on research and clinical care in gastrointestinal and liver disorders. To learn more about their work, visit Digestive Diseases.