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The Journal of Neuroscience, April 8, 2009, 29(14):4519-4530; doi:10.1523/JNEUROSCI.3863-08.2009

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Cellular/Molecular
Targeting of Acetylcholinesterase in Neurons In Vivo: A Dual Processing Function for the Proline-Rich Membrane Anchor Subunit and the Attachment Domain on the Catalytic Subunit

Alexandre Dobbertin,^1,2 Anna Hrabovska,^1,2 Korami Dembele,⁴ Shelley Camp,³ Palmer Taylor,³ Eric Krejci,^1,2 and Véronique Bernard^1,2

¹Université Paris Descartes, 75006 Paris, France, ²Inserm U686, Paris, France ³Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0657, and ⁴Ecole Normale supérieure, Centre Nationale de la Recherche Scientifique, Unité Mixte de Recherche 8544, 75006 Paris, France

Correspondence should be addressed to either Véronique Bernard or Eric Krejci at the above address. Email: veronique.bernard{at}univ-paris5.fr; or Email: eric.krejci{at}univ-paris5.fr

Acetylcholinesterase (AChE) accumulates on axonal varicosities and is primarily found as tetramers associated with a proline-rich membrane anchor (PRiMA). PRiMA is a small transmembrane protein that efficiently transforms secreted AChE to an enzyme anchored on the outer cell surface. Surprisingly, in the striatum of the PRiMA knock-out mouse, despite a normal level of AChE mRNA, we find only 2–3% of wild type AChE activity, with the residual AChE localized in the endoplasmic reticulum, demonstrating that PRiMA in vivo is necessary for intracellular processing of AChE in neurons. Moreover, deletion of the retention signal of the AChE catalytic subunit in mice, which is the domain of interaction with PRiMA, does not restore AChE activity in the striatum, establishing that PRiMA is necessary to target and/or to stabilize nascent AChE in neurons. These unexpected findings open new avenues to modulating AChE activity and its distribution in CNS disorders.

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Received Aug. 14, 2008; revised Jan. 15, 2009; accepted Jan. 19, 2009.

Correspondence should be addressed to either Véronique Bernard or Eric Krejci at the above address. Email: veronique.bernard{at}univ-paris5.fr; or Email: eric.krejci{at}univ-paris5.fr

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