Cell reportsJul 29, 2026

Neuronal activity screening links TMEM50A-related cell recycling to healthy synapses and long-term memory

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

TMEM50A is identified as an essential regulator of neuronal activity.

A high-throughput platform was established that combines calcium-integrating sensors with CRISPRi screening in human-derived neurons.
This approach allows for systematic screening of memory-associated genes, leading to the recovery of known regulators.
TMEM50A was found to form a complex with LEPROTL1 and is associated with machinery involved in the processing of cellular vesicles.
Loss of TMEM50A impairs the function of multivesicular bodies, which are crucial for cellular communication.
Consequences of TMEM50A loss include a remodeled neuronal surface proteome, reduced synapse density, and altered behavior in mice.

Simplified

While advances in omics profiling rapidly expand the catalog of genes associated with brain activity in health and disease, functional annotation lags 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 through pooled screening. Using a focused library of memory-associated genes, we recover known regulators and identify TMEM50A, a previously uncharacterized protein, as an essential regulator of neuronal activity. TMEM50A forms a complex with LEPROTL1 and associates with ESCRT-III machinery on multivesicular bodies (MVBs). TMEM50A loss impairs MVBs 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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PubMed

Neuronal activity screening links TMEM50A-related cell recycling to healthy synapses and long-term memory

Abstract

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