Tauopathy in Drosophila: Neurodegeneration Without Neurofibrillary Tangles Curtis W.Wittmann, Matthew F. Wszolek, Joshua M. Shulman, Paul M. Salvaterra, Jada Lewis, Mike Hutton, Mel B. Feany

Curtis W. Wittmann,¹ Matthew F. Wszolek,¹ Joshua M. Shulman,¹ Paul M. Salvaterra,² Jada Lewis,³ Mike Hutton,³ Mel B. Feany^1*

¹Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Room 514, Boston, MA 02115, USA. ²Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA. ³Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.

*To whom correspondence should be addressed: E-mail: mel_feany@hms.harvard.edu

To extend analysis of cell type specificity of neurotoxicity produced by human tau in Drosophila we expressed tau specifically in motor neurons (D42-GAL4; 20). In contrast to cholinergic neurons, motor neurons are seldom affected in Alzheimer's disease, although motor neurons may be affected in tauopathies like the amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. The major flight motor neurons in the thoracic ganglion were identified by -galactosidase (-gal) immunostaining in one day old control flies (Web fig. 1A). The same group of motor neurons was preserved in aged control (Web fig. 1B) and tau transgenic flies (Web fig. 1C-D). The enhanced toxicity of tau to cholinergic versus motor neurons likely does not reflect differences in the amount of tau produced in the two types of neurons (18). These findings suggest that motor neurons were relatively preserved in tau transgenic flies. The mechanism underlying relative anatomic specificity in neurodegenerative diseases remains mysterious.

Supplemental Figure 1. Motor neurons are preserved in tau transgenic flies. (A and B) -gal immunoreactivity identifies normal motor neurons in control animals at one day (A) and 45 days (B). Genotype: UAS-lacZ / +; D42-GAL4 / +. (C and D) Motor neurons are well preserved in 45 day old flies expressing wt (C) or R406W mutant (D) tau. Genotypes: UAS-wt tau 1 / UAS-lacZ; D42-GAL4 / +, UAS-lacZ / +; UAS-R406W tau 2 / D42-GAL4. Arrows in (A) and (D) highlight prominent nucleoli. Scale bar, 10 m.

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Specificity for cholinergic neurons in human tau transgenic flies, as in Alzheimer's disease, is relative rather than absolute. Expressing human tau in photoreceptors produced neurotoxicity. When wt human tau (Web fig. 2A) and R406W mutant tau (Web fig. 2B) were expressed at equivalent levels in photoreceptor cells, the normal architecture of the eye was disrupted in flies expressing mutant tau, producing a rough eye phenotype. Expression of V337M mutant tau in photoreceptors also produced a rough eye phenotype.

Supplemental Figure 2. Expression of mutant human tau in photoreceptor cells causes a rough eye phenotype. (A) The eye of flies expressing wt tau protein is normal in size and shows a regular arrangement of ommatidia. Genotype: elav-GAL4 / +; UAS-wt tau 1 / +. (B) Flies expressing an equivalent amount of R406W mutant tau protein show a mild decrease in eye size and roughening of the eye. Genotype: elav-GAL4 / +; UAS-R406W 1 tau / +.

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