A new study identified a group of genes that may be involved in the development and severity of Gaucher disease. Researcher also found that memantine, a drug used in the treatment of Alzheimer’s disease, increased the life span of animal models with Gaucher disease (GD).
The study, titled “Identification of Modifier Genes in a Mouse Model of Gaucher Disease,” by Andrés Klein, from the Telethon Institute of Genetics and Medicine in Italy, and his colleagues, was published in the journal Cell Reports.
Although GD is caused by mutations in a single gene (GBA1), patients can have a wide variety of symptoms with the presence or absence of aggressive neurological disease (nGD), which makes it difficult to identify the possible association between a given mutation and specific symptoms.
Researchers thought to identify the genes that are altered when metabolic deficits are triggered by the loss of the enzyme defective in GD (acid β-glucosidase). That action could explain the molecular mechanisms underlying the different symptom sets among patients with similar GD mutations.
To do so, researchers induced GD in different strains of inbred mice by injecting a low dose of a chemical inhibitor of acid β-glucosidase. They then analyzed the genetic profile of the animals that were more or less susceptible to die after developing neurological problems associated with GD.
“Strains with a short lifespan had pronounced motor defects, whereas those with a longer lifespan developed motor abnormalities at a later age,” the authors wrote in the report. “Moreover, mice that lived for a short time displayed activated microglia in layer V of the cortex, an area that shows significant pathology in mouse models of nGD. Few, if any, activated microglia were detected in the same region in long-lived strains, even at later stages of the disease, suggesting that mice with a long lifespan may die from non-neurological disease.”
Of the many genes identified as possibly involved in the susceptibility or resistance of the animals, some belong to a group of important players in the communication between neurons. The gene Grin2b encodes NR2B, a protein that composes the NMDA receptors, one of the most important receptors for the proper functioning of neurons. The researchers found that short-lived mice presented increased levels of NR2B in the brain.
To check whether the levels of NR2B could influence lifespan, the researchers treated the animals from short-lived strains with memantine, a drug that inhibits NMDA receptors and is used to treat Alzheimer’s. The susceptible animals presented a delay in the progression of motor symptoms and in the appearance of inflammation markers. The also lived longer.
Researchers observed that brain samples from GD patients who had died also had increased levels of NR2B, which further supported that high levels of the protein may play a toxic role in GD.
“One of the most noteworthy findings from our study is the possible use of memantine as a therapy for nGD,” the authors wrote. “Whether memantine could be used as a therapeutic option in human nGD patients remains to be established.”