title: Monoamine oxidase-A physically interacts with presenilin-1(M146V) in the mouse cortex.
abstract: The concentration of presenilin-1 (PS-1) protein at the mitochondrial-associated aspect of the endoplasmic reticulum supports the potential for a mitochondrial influence of PS-1. Given that carriers of certain Alzheimer's disease (AD)-related PS-1 variants are predisposed to clinical depression and that depression has been historically associated with the mitochondrial enzyme, monoamine oxidase-A (MAO-A), we investigated cortical MAO-A function in the AD-related PS-1(M146V) knock-in mouse. The MAO-A system was clearly altered in the PS-1(M146V) mouse as revealed by (a) a mismatch between MAO-A protein expression and MAO-A activity; (b) changes in MAO-A-mediated monoaminergic neurotransmitter metabolism; (c) changes in non-cognitive behavior following treatment with the irreversible MAO-A inhibitor clorgyline; and (d) an increase in the potency of clorgyline in these same mice. We next investigated whether PS-1(M146V) could be influencing MAO-A directly. We observed (a) an enhanced MAO-A activity in necropsied PS-1(M146V) mouse cortical extracts incubated with DAPT (a PS-1 substrate-competitor); (b) the proximity of PS-1 with MAO-A and mitochondrial markers in cortical sections and in primary cortical neurons; (c) the co-segregation and co-immunoprecipitation of PS-1 and MAO-A within the mitochondrial fraction; and (d) the co-immunoprecipitation of overexpressed PS-1(M146V) and MAO-A proteins from N2a lysates. The PS-1(ΔEx9) and PS-1(D257A) variants, known to have low substrate-binding capacity, co-immunoprecipitated weakly with MAO-A. These combined data support a physical interaction between PS-1 and MAO-A that could influence MAO-A activity and contribute to the monoaminergic disruptions common to disorders as seemingly diverse as depression and AD.
authors: Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
authors: Zelan
authors: Z
authors: Wei
authors: Geraldine G
authors: GG
authors: Gabriel
authors: Lewei
authors: L
authors: Rui
authors: Xia
authors: X
authors: Cao
authors: Paul R
authors: PR
authors: Pennington
authors: Jennifer
authors: J
authors: Chlan-Fourney
authors: Adil J
authors: AJ
authors: Nazarali
authors: Glen B
authors: GB
authors: Baker
authors: Darrell D
authors: DD
authors: Mousseau
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003010:Clorgyline / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D018377:Neurotransmitter Agents / Q000378:metabolism; D009930:Organic Chemicals; D053764:Presenilin-1 / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D013550:Swimming / Q000523:psychology; D014162:Transfection; D014633:Valine / Q000235:genetics*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C507919:MitoTracker Red 580; D008996:Monoamine Oxidase Inhibitors; D018377:Neurotransmitter Agents; D009930:Organic Chemicals; D053764:Presenilin-1; D050994:Voltage-Dependent Anion Channels; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008715:Methionine; D008995:Monoamine Oxidase; D014633:Valine; D003010:Clorgyline