mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis.

Loss of TSC2 in neural progenitors causes cell-autonomous formation of reactive astrocytes with neurodegenerative features in tuberous sclerosis.

• Why it matters: Understanding whether glial abnormalities are a cause or consequence of TSC-related pathology is crucial for developing targeted therapies for neurodevelopmental disorders like TSC.
• What they did: Using human brain organoids and patient tissue, the study employed single-cell transcriptomics and immunostaining to show that TSC2 deficiency biases progenitors to become enlarged, pro-inflammatory astrocytes independently of seizures.
• The result: Reactive astrocytes exhibit reduced glutamate transporter expression, increased inflammatory cytokines, and elevated neurodegenerative risk genes, suggesting glial dysfunction actively drives TSC pathology and offers new therapeutic avenues.