L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms.
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L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms. / Schäfer, Michael K E; Nam, Yun-Chung; Moumen, Anice; Keglowich, Laura; Bouché, Elisabeth; Küffner, Mercedes; Bock, Hans H; Rathjen, Fritz G; Raoul, Cedric; Frotscher, Michael.
In: NEUROBIOL DIS, Vol. 40, No. 1, 1, 2010, p. 222-237.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms.
AU - Schäfer, Michael K E
AU - Nam, Yun-Chung
AU - Moumen, Anice
AU - Keglowich, Laura
AU - Bouché, Elisabeth
AU - Küffner, Mercedes
AU - Bock, Hans H
AU - Rathjen, Fritz G
AU - Raoul, Cedric
AU - Frotscher, Michael
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Rats
KW - Mutation genetics
KW - Syndrome
KW - Rats, Wistar
KW - Endoplasmic Reticulum metabolism
KW - Neurons metabolism
KW - Cell Line
KW - Organ Culture Techniques
KW - CA3 Region, Hippocampal metabolism
KW - Cell Membrane metabolism
KW - Cell Polarity genetics
KW - Neural Cell Adhesion Molecule L1 genetics
KW - Neurogenesis genetics
KW - Protein Transport genetics
KW - Animals
KW - Humans
KW - Rats
KW - Mutation genetics
KW - Syndrome
KW - Rats, Wistar
KW - Endoplasmic Reticulum metabolism
KW - Neurons metabolism
KW - Cell Line
KW - Organ Culture Techniques
KW - CA3 Region, Hippocampal metabolism
KW - Cell Membrane metabolism
KW - Cell Polarity genetics
KW - Neural Cell Adhesion Molecule L1 genetics
KW - Neurogenesis genetics
KW - Protein Transport genetics
M3 - SCORING: Zeitschriftenaufsatz
VL - 40
SP - 222
EP - 237
JO - NEUROBIOL DIS
JF - NEUROBIOL DIS
SN - 0969-9961
IS - 1
M1 - 1
ER -
