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.
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.
Dobbertin
Alexandre
A
Université Paris Descartes, Paris, France.
Hrabovska
Anna
A
Dembele
Korami
K
Camp
Shelley
S
Taylor
Palmer
P
Krejci
Eric
E
Bernard
Véronique
V
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D020134:Catalytic Domain / Q000502:physiology*; D002460:Cell Line; D004795:Enzyme Stability / Q000502:physiology; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C486718:prima1 protein, mouse; D000110:Acetylcholinesterase