A Pooled Neuronal Activity Screen Links TMEM50A-Dependent MVB Function to Synaptic Integrity and Remote Memory
摘要
While advances in omics profiling have rapidly expanded the catalog of genes associated with brain activity in health and disease, functional annotation has lagged far behind. Here, we establish a high-throughput functional genomics platform that couples the calcium-integrating sensor CaMPARI2 with CRISPRi screening in human iPSC-derived neurons. By converting cumulative neuronal activity into a stable, flow cytometry–readable signal, this approach enables systematic interrogation of neuronal activity through pooled screening. Using a focused library of memory-associated genes, we recover known regulators and identify TMEM50A, a previously uncharacterized protein, as essential for neuronal activity. TMEM50A forms a complex with LEPROTL1 and associates with ESCRT-III machinery on multivesicular bodies (MVBs). TMEM50A loss impairs MVB function, remodels the neuronal surface proteome, reduces synapse density, and alters behavior in mice. This platform enables systematic discovery of neuronal activity regulators and reveals a critical role for TMEM50A-dependent MVB function in maintaining synaptic integrity and behavior.
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- 2026-01-22 (2)
- 2026-01-22 (1)
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