The neurotransmitter glutamate is essential for regulating everything from mood to memory, but it can also encourage a toxic buildup of protein, which can contribute to Alzheimer’s and related diseases. In a USC Stem Cell-led study published in Neuron, scientists describe a new approach for counteracting these devastating and often fatal neurodegenerative effects. Researchers made their discovery by studying lab mice as well as human brain “organoids,” which are rudimentary brain-like structures grown in the lab. The scientists produced these organoids from stem cells derived from healthy people as well as from patients with neurodegenerative diseases related to tau toxicity. When exposed to glutamate, the organoids—particularly the ones derived from patients with neurodegenerative diseases—exhibited a toxic buildup of tau protein as well as neurodegeneration and nerve cell death. Mice with a mutation in tau, which causes a common form of dementia, displayed similar pathologies. Many potential drugs have been developed to mitigate the neurodegenerative effects of glutamate toxicity, but they’ve had mixed results in clinical trials. Taking a different approach, the scientists screened for genes that respond to glutamate and identified a gene called KCTD20. When the scientists suppressed the activity of this gene in the organoids and in the mice, glutamate did not produce the same ill effects in terms of either tau buildup or neurodegeneration. Through additional experiments, the team discovered that suppressing this gene activated cellular compartments called lysosomes, which enveloped the toxic tau proteins and expelled them from the organoids’ cells.
