title: Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition.
abstract: Misfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing 4 microtubule-binding repeats and 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. Most important, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies.
authors: Department of Translational Science and Molecular Medicine, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA; Marine Biological Laboratory, Woods Hole, MA, USA; California National Primate Research Center, University of California, Davis, CA, USA.
authors: Kristine
authors: K
authors: Cox
authors: Department of Translational Science and Molecular Medicine, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA; Marine Biological Laboratory, Woods Hole, MA, USA.
authors: Benjamin
authors: B
authors: Combs
authors: Marine Biological Laboratory, Woods Hole, MA, USA.
authors: Brenda
authors: B
authors: Abdelmesih
authors: Marine Biological Laboratory, Woods Hole, MA, USA; Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
authors: Gerardo
authors: G
authors: Morfini
authors: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA; Marine Biological Laboratory, Woods Hole, MA, USA.
authors: Scott T
authors: ST
authors: Brady
authors: Department of Translational Science and Molecular Medicine, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA; Neuroscience Program, Michigan State University, East Lansing, MI, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI, USA. Electronic address: Nicholas.kanaan@hc.msu.edu.
authors: Nicholas M
authors: NM
authors: Kanaan
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport; D049832:Decapodiformes; D006801:Humans; D066298:In Vitro Techniques; D058105:Polymerization; D066329:Protein Aggregates; D000072417:Protein Domains; D020033:Protein Isoforms; D015398:Signal Transduction; D024801:Tauopathies / Q000209:etiology* / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D066329:Protein Aggregates; D020033:Protein Isoforms; D016875:tau Proteins
keywords: Aggregation; Alzheimer's disease; Axon; Microtubule-associated protein; Oligomer; Pathological conformations; Tauopathy