L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms

Neurobiology of Disease
Michael SchäferMichael Frotscher

Abstract

Mutations in the human L1CAM gene cause neurodevelopmental disorders collectively referred to as L1 syndrome. Here, we investigated cellular pathomechanisms underlying two L1 syndrome mutations, R184Q and W1036L. We demonstrate that these mutations cause partial endoplasmic reticulum (ER) retention of L1, reduce L1 cell surface expression, but do not induce ER stress in neuronal NSC-34 cells. We provide evidence that surface trafficking of mutated L1 is affected by defective sorting to ER exit sites and attenuated ER export. However, in differentiated neuronal cultures and long-term cultured hippocampal slices, the L1-R184Q protein is restricted to cell bodies, whereas L1-W1036L also aberrantly localizes to dendrites. These trafficking defects preclude axonal targeting of L1, thereby affecting L1-mediated axon growth and arborization. Our results indicate that L1 syndrome mutations impair neuronal L1 function at different levels, firstly by attenuating ER export and secondly by interfering with polarized neuronal trafficking.

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Citations

Mar 1, 2012·Cell and Tissue Research·Michael K E Schäfer, Michael Frotscher
Feb 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Xiaowei DouMichael E Charness
Dec 17, 2011·The Journal of Biological Chemistry·Gail K SeaboldRobert J Wenthold
Oct 14, 2010·FEBS Letters·Michael K E SchäferSimone Diestel
Sep 7, 2011·Advanced Drug Delivery Reviews·Christian PlankOlga Mykhaylyk
Mar 24, 2016·The Journal of Experimental Medicine·Christopher PatzkeThomas C Südhof
Jan 28, 2014·Experimental Cell Research·Marie-Marcelle Trinh-Trang-TanEkaterini Kordeli
Dec 1, 2017·Nature Neuroscience·Or A ShemeshValentina Emiliani

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