Exonic Point Mutations of Human Tau Enhance its Toxicity and Cause Characteristic Changes in Neuronal Morphology, Tau Distribution and Tau Phosphorylation in the Lamprey Cellular Model of Tauopathy

Article type: Research Article

Authors: Lee, Sangmook^a | Jung, Cheolwha^a | Lee, Gloria^b | Hall, Garth F.^{a; *}

Affiliations: [a] Center for Cellular Neuroscience and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA | [b] Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

Correspondence: [*] Corresponding author: Garth F. Hall, Department of Biological Sciences, University of Massachusetts Lowell, One University Ave., Lowell, MA 01854, USA. Tel.: +1 978 934 2893; Fax: +1 978 934 3044; E-mail: Garth_Hall@uml.edu.

Note: [] Communicated by Jesus Avila

Abstract: Exonic mutations in the gene coding for human tau cause familial neurofibrillary degenerative diseases (tauopathies) which exhibit mutation-specific characteristics. It is thus unclear whether such mutations have similar effects on tau structure and function in vivo and if they act via similar cytopathological mechanisms in vulnerable neuron types. We have previously shown that overexpressing wild type human tau isoforms in identified giant neurons (ABCs) of the lamprey CNS results in characteristic, stereotyped cytopathological changes in these cells over several weeks. Here, we use this model to compare the cytopathological consequences of expressing wild type and exonic mutant tau isoforms (P301L, G272V, V337M, and R406W) at a high level of resolution. We show that each of the four exonic htau mutations tested accelerate degeneration in ABCs when compared to their WT parent isoforms, and that the patterns of human tau distribution, phosphorylation and cytopathology, while similar, vary characteristically from one another among both WT and mutant isoforms in a single identified neuron in situ. Our results therefore suggest that at least some of the differences between the effects of these mutations in humans are due to cell autonomous, mutation specific differences in the cytopathological mechanism of tau-induced neurodegeneration.

Keywords: Exonic mutation, human tau, in situ cellular model, tauopathy

DOI: 10.3233/JAD-2009-0954

Journal: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 99-111, 2009