title: Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport.
abstract: Tau protein is present in six different splice forms in the human brain and interacts with microtubules via either 3 or 4 microtubule binding repeats. An increased ratio of 3 repeat to 4 repeat isoforms is associated with neurodegeneration in inherited forms of frontotemporal dementia. Tau over-expression diminishes axonal transport in several systems, but differential effects of 3 repeat and 4 repeat isoforms have not been studied. We examined the effects of tau on mitochondrial transport and found that both 3 repeat and 4 repeat tau change normal mitochondrial distribution within the cell body and reduce mitochondrial localization to axons; 4 repeat tau has a greater effect than 3 repeat tau. Further, we observed that the 3 repeat and 4 repeat tau cause different alterations in retrograde and anterograde transport dynamics with 3 repeat tau having a slightly stronger effect on axon transport dynamics. Our results indicate that tau-induced changes in axonal transport may be an underlying theme in neurodegenerative diseases associated with isoform specific changes in tau's interaction with microtubules.
authors.affiliation: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Stoothoff
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Jones
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.forename: Daniel
authors.initials: D
authors.lastname: Joyner
authors.forename: Ekta
authors.initials: E
authors.lastname: Chhabra
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bercury
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Fan
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.forename: Brian
authors.initials: B
authors.lastname: Bacskai
authors.forename: Jon
authors.initials: J
authors.lastname: Edd
authors.forename: Daniel
authors.initials: D
authors.lastname: Irimia
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000166:cytology; D005910:Glioma; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D046210:Microfluidic Analytical Techniques; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D012091:Repetitive Sequences, Nucleic Acid / Q000502:physiology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D014162:Transfection; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D049452:Green Fluorescent Proteins
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