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.
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.
Lee
Sangmook
S
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA.
Jung
Cheolwha
C
Lee
Gloria
G
Hall
Garth F
GF
D000818:Animals; D003712:Dendrites / Q000473:pathology; D005091:Exons / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007798:Lampreys / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology*; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics* / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
C054369:MAPT protein, human; D016875:tau Proteins