2025-01-28 コロンビア大学
<関連情報>
- https://cancerdynamics.columbia.edu/news/new-study-uncovers-how-gliomas-disrupt-brain-function-and-points-rapid-therapeutic-reversal
- https://www.sciencedirect.com/science/article/pii/S0896627324009267?dgcid=coauthor
神経膠腫が誘発する興奮性ニューロンの変化はmTOR阻害によって逆転する Glioma-induced alterations in excitatory neurons are reversed by mTOR inhibition
Alexander R. Goldberg, Athanassios Dovas, Daniela Torres, Brianna Pereira, Ashwin Viswanathan, Sohani Das Sharma, Angeliki Mela, Edward M. Merricks, Cristina Megino-Luque, Julie J. McInvale, Markel Olabarria, Leila Abrishami Shokooh, Hanzhi T. Zhao, Cady Chen, Corina Kotidis, Peter Calvaresi, Matei A. Banu, Aida Razavilar, Tejaswi D. Sudhakar, Ankita Saxena …Peter Canoll
Neuron Available online: 20 January 2025
DOI:https://doi.org/10.1016/j.neuron.2024.12.026
Graphical abstract
Highlights
- Glioma activates neuronal mTOR and alters translation of synaptic/spine genes
- Neurons at the glioma margin show loss of dendritic spines and inhibitory synapses
- GCaMP imaging reveals neuronal hyperexcitability and stimulus-evoked discharges
- AZD8055 reverses these glioma-induced changes and normalizes neuronal activity
Summary
Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed these tumor-induced changes. These findings reveal mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma and suggest new strategies for treating glioma-associated neurological symptoms.
