Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport

• Published in: Journal of neurochemistry 2009-10, Vol.111 (2), p.417-427
• Main Authors: Stoothoff, Will, Jones, Phillip B, Spires-Jones, Tara L, Joyner, Daniel, Chhabra, Ekta, Bercury, Kathryn, Fan, Zhanyun, Xie, Hong, Bacskai, Brian, Edd, Jon, Irimia, Daniel, Hyman, Bradley T
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer disease; Alzheimer’s disease; Animals; axonal transport; Axonal Transport - physiology; Binding sites; Biochemistry; Biological and medical sciences; Brain; Cell Line, Tumor; Cerebral Cortex - cytology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Glioma; Green Fluorescent Proteins - genetics; Humans; Medical sciences; Mice; Microfluidic Analytical Techniques; mitochondria; Mitochondria - physiology; Neurology; Neurons - cytology; Neurons - physiology; Organic mental disorders. Neuropsychology; Protein Transport - physiology; Proteins; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Repetitive Sequences, Nucleic Acid - physiology; tau; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - genetics; Tauopathies - metabolism; Tauopathies - physiopathology; tauopathy; Transfection
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06316.x

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.