Readthrough acetylcholinesterase in inflammation-associated neuropathies.
The cholinergic control over inflammatory reactions calls for deciphering the corresponding protein partners. An example is blood-nerve barrier disruption allowing penetration of inflammatory factors, which is notably involved in various neuropathies due to yet unknown molecular mechanism(s). In rats, lipopolysaccharide (LPS) administration followed by intra-neural (i.n.) saline injection inducing a focal blood-nerve disruption leads to systemic inflammatory reaction accompanied by transient conduction impairment in the sciatic nerve. Here, we provide evidence compatible with the hypothesis that ARP, the naturally cleavable C-terminal peptide of the stress-induced "readthrough" acetylcholinesterase variant (AChE-R), is causally involved in the emergence of this LPS-induced conduction impairment. Intra-neural injection to naïve rats of conditioned medium from cultured splenocytes exposed to LPS in vitro (reactive splenocyte medium) induced a transient conduction impairment that was accompanied by facilitated accumulation of cleaved intra-neural ARP. Protein kinase C (PKC) betaII, known to interact with ARP, was significantly elevated in the LPS-exposed sciatic nerve preparations. Moreover, direct i.n. injection of synthetic ARP30, bearing the mouse AChE-R C-terminal sequence, similarly induced PKCbetaII expression and conduction impairment. The induction of neural conduction impairment by ARP, possibly through its interaction with PKCbetaII, suggests a role for AChE-R expression in inflammation-associated neuropathies.
Dori
Amir
A
Department of Neurology, The Joseph Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel.
Ifergane
Gal
G
Saar-Levy
Tal
T
Bersudsky
Marina
M
Mor
Inbal
I
Soreq
Hermona
H
Wirguin
Itzhak
I
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D015151:Immunoblotting; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009132:Muscles / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D017077:Culture Media, Conditioned; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011950:Receptors, Cholinergic; D000110:Acetylcholinesterase; D000109:Acetylcholine