A drug approved to treat amyotrophic lateral sclerosis (ALS), riluzole, could slow the gradual loss of Purkinje neurons that occurs in Niemann-Pick disease type C1 (NPC1), according to a laboratory study by scientists at the National Institutes of Health (NIH). Mice with NPC1 survived 12% longer when treated with riluzole, compared to untreated mice. The researchers believe that riluzole or similar drugs may provide a way to slow disease progression in NPC1 patients.
The study was conducted by Forbes D. Porter, M.D., Ph.D., of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues in the National Human Genome Research Institute and National Institute of Arthritis and Musculoskeletal and Skin Disease. Their report appears in Molecular Genetics and Metabolism.
NPC1 is a rare, progressive, lethal, neurodegenerative disorder caused by endolysosomal storage of unesterified cholesterol. Progressive loss of cerebellar Purkinje neurons is caused by impaired passage of cholesterol through cells. This leads to difficulty controlling movements, liver and lung disease, impaired swallowing, intellectual decline, and death.
This condition affects 1 in 100,000 to 120,000 births, and symptoms can arise right after birth or later. NPC is caused by mutations in the NPC1 gene (NPC type 1C) or the NPC2 gene (NPC type 2C). NPC1 is by far the most common, accounting for 95% of cases. Early symptoms include developmental delay and regression, as children grow, they may exhibit clumsiness, unsteady gait, and slurred speech. By the teen or adult phase, they may show psychiatric symptoms and progressive cognitive impairment.
It’s believed much of the movement difficulties in NPC1 result from the gradual loss of Purkinje neurons. In this study, researchers found that mice with a form of NPC1 have a diminished ability to lower levels of glutamate after it has bound to a neuron’s surface. Glutamate is an excitatory neurotransmitter, and elevated extracellular levels of this molecule can be neurotoxic. Porter and his colleagues believe the buildup of glutamate contributes to the brain cell loss and that riluzole, which acts in ALS by blocking the release of glutamate, could delay progression of NPC1 as well.
Comparing single cell RNAseq data from control (Npc1+/+) and mutant (Npc1−/−) mice, the researchers found significantly decreased expression of Slc1a3 in Npc1-/- astrocytes. Slc1a3 encodes a glutamate transporter (GLAST, EAAT1) which decreases glutamate concentrations in the post synaptic space after neuronal firing.
Further, the team showed that decreased expression of Slc1a3 in Npc1−/− mice decreases surface protein expression and glutamate uptake in their astrocytes.
The team then treated NPC1 deficient mice with ceftriaxone and riluzole. Ceftriaxone is a β-lactam antibiotic that upregulates the expression of Slc1a2, an alternative glial glutamate transporter. Although ceftriaxone increased Slc1a2 expression, no treatment effect was observed in the NPC1 mice.
Riluzole is a glutamate receptor antagonist that inhibits postsynaptic glutamate signaling and thereby reduces its release. The team found that treatment with riluzole increased median survival in Npc1−/− by 12%.
They write that, “Given that riluzole is an approved drug for the treatment of amyotrophic lateral sclerosis, repurposing of this drug may provide a novel therapeutic approach to decrease disease progression in Niemann-Pick disease type, C1 patients.”