title: Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease.
abstract: The p62/sequestosome-1 is a multifunctional protein containing several protein-protein interaction domains. Through these interactions p62 is involved in the regulation of cellular signaling and protein trafficking, aggregation and degradation. p62 protein can bind through its UBA motif to ubiquitinated proteins and control their aggregation and degradation via either autophagy or proteasomes. p62 protein has been reported to be seen in association with the intracellular inclusions in primary and secondary tauopathies, α-synucleinopathies and other neurodegenerative brain disorders displaying inclusions with misfolded proteins. In Alzheimer's disease (AD), p62 protein is associated with neurofibrillary tangles composed primarily of hyperphosphorylated tau protein and ubiquitin. Increasing evidence indicates that p62 has an important role in the degradation of tau protein. The lack of p62 protein expression provokes the tau pathology in mice. Recent studies have demonstrated that the p62 gene expression and cytoplasmic p62 protein levels are significantly reduced in the frontal cortex of AD patients. Decline in the level of p62 protein can disturb the signaling pathways of Nrf2, cyclic AMP and NF-κB and in that way increase oxidative stress and impair neuronal survival. We will review here the molecular and functional characteristics of p62 protein and outline its potential role in the regulation of Alzheimer's pathogenesis.
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. antero.salminen@uef.fi
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D006801:Humans; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D016875:tau Proteins