title: Increased association between rough endoplasmic reticulum membranes and mitochondria in transgenic mice that express P301L tau.
abstract: In several neurodegenerative diseases, including Alzheimer disease, the neuronal microtubule-associated protein tau becomes hyperphosphorylated, accumulates in the somatodendritic compartment, and aggregates into insoluble filaments. The consequences of the accumulation of hyperphosphorylated tau in the somatodendritic compartment remain poorly characterized at the early stage of disease before the formation of tau insoluble filaments. We investigated the ultrastructural changes induced by this accumulation in the neuronal soma of motor neurons in asymptomatic JNPL3 mice that overexpress mutant tau, P301L. More numerous contacts between rough endoplasmic reticulum (RER) membranes and mitochondria were observed in JNLP3 mice compared with wild-type mice. This correlated with a preferential increase of the amount of tau at the surface of RER membranes but not at the surface of mitochondria, as revealed by tau immunogold labeling. Using a subcellular fractionation procedure, an increased amount of phosphorylated tau was identified in the rough microsome subfraction, wherein the RER marker, ribophorin, was enriched. A similar increase was noted in the rough microsome subfraction isolated from Alzheimer disease brains. The association of hyperphosphorylated tau with ER membranes was confirmed by double immunogold labeling of the subfraction enriched in ER membranes isolated from Alzheimer disease brains. These results suggest that more contacts between RER membranes and mitochondria resulting from the accumulation of tau at the surface of RER membranes might contribute to tau-induced neurodegeneration.
authors.affiliation: Departement de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Perreault
authors.forename: Olivier
authors.initials: O
authors.lastname: Bousquet
authors.forename: Michel
authors.initials: M
authors.lastname: Lauzon
authors.forename: Jacques
authors.initials: J
authors.lastname: Paiement
authors.forename: Nicole
authors.initials: N
authors.lastname: Leclerc
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007930:Leucine / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D011392:Proline / Q000235:genetics*; D050765:Qa-SNARE Proteins / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D013116:Spinal Cord / Q000648:ultrastructure; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C064459:KDEL receptor; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; C085349:PHF-1 monoclonal antibody; D050765:Qa-SNARE Proteins; D018000:Receptors, Peptide; D016875:tau Proteins; D011392:Proline; D007930:Leucine