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bioRxiv · 10.1101/2025.03.02.641041

TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons

Flores-Mendez, M.·Tintos-Hernandez, J. A.·Ramos-Rodriguez, L.·Miles, L.·Lo, T. Y.·Song, Y.·Ortiz-Gonzalez, X. R.
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Abstract

Monogenic pediatric neurodegenerative disorders can reveal fundamental cellular mechanisms that underlie selective neuronal vulnerability. TBCK-Encephaloneuronopathy (TBCKE) is a rare autosomal recessive disorder caused by stop-gain variants in the TBCK gene. Clinically, patients show evidence of profound neurodevelopmental delays, but also symptoms of progressive encephalopathy and motor neuron disease. Yet, the physiological role of TBCK protein remains unclear. We report a human neuronal TBCKE model, derived from iPSCs homozygous for the Boricua variant (p.R126X). Using unbiased proteomic analyses of human neurons, we find TBCK interacts with PPP1R21, C12orf4, and Cryzl1, consistent with TBCK being part of the FERRY mRNA transport complex. Loss of TBCK leads to depletion of C12ORF4 protein levels across multiple cell types, suggesting TBCK may also play a role regulating at least some members of the FERRY complex. We find that TBCK preferentially, but not exclusively, localizes to the surface of endolysosomal vesicles and can colocalize with mRNA in lysosomes. Furthermore, TBCK-deficient neurons have reduced mRNA content in the axonal compartment relative to the soma. TBCK-deficient neurons show reduced levels of the lysosomal dynein/dynactin adapter protein JIP4, which functionally leads to TBCK-deficient neurons exhibiting striking lysosomal axonal retrograde trafficking defects. Hence, our work reveals that TBCK can mediate endolysosomal trafficking of mRNA, particularly along lysosomes in human axonal compartments. TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in neurons, which likely contribute to the preferential susceptibility to neurodegeneration.

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Flores-Mendez, M., Tintos-Hernandez, J. A., Ramos-Rodriguez, L., Miles, L., Lo, T. Y., Song, Y., Ortiz-Gonzalez, X. R.. 2025-03-07. TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons. https://doi.org/10.1101/2025.03.02.641041

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