Tauopathy in Drosophila : Neurodegeneration Without Neurofibrillary Tangles

Abstract

The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly Drosophila melanogaster. Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

“…It appears that soluble hyperphosphorylated tau can contribute to nerve cell dysfunction prior to assembly into filaments. This is reminiscent of Drosophila and Caenorhabditis elegans lines expressing human wild-type or mutant tau, in which nerve cell loss and a reduced lifespan are observed, in the apparent absence of tau filaments (Wittmann et al 2001;Kraemer et al 2003). In genetic modifier screens in Drosophila, an increase in kinase activity enhanced tau toxicity, whereas an increase in phosphatase activity was beneficial (Feany et al 2010).…”

‘Functional DNA array’ in the fly: implication for neuronal degeneration

“…14,15 Given that an APP695-Swedish fly has been generated, 16 it would be interesting to examine the neuropathology of a mutant tau/APP695-Swedish double transgenic fly. In these fly models for Parkinson's and Alzheimer's diseases, the ectopic expression of a mutant form of human tau or a-synuclein can cause a rough-eye phenotype or photoreceptor cell degeneration, 10,11 indicating their practical application for a large-scale GOF screen.…”

“…13 As done for the mouse model, the fly model of tauopathies was generated by expressing mutant tau (R406W or V337M). 11 Pan-neuronal expression of mutant tau in flies resulted in late-onset neurodegeneration, early death, and the accumulation of abnormal tau but not NFTs. 11 These neuropathological phenotypes were observed preferentially but not absolutely in cholinergic neurons.…”

“…11 Pan-neuronal expression of mutant tau in flies resulted in late-onset neurodegeneration, early death, and the accumulation of abnormal tau but not NFTs. 11 These neuropathological phenotypes were observed preferentially but not absolutely in cholinergic neurons. In the mouse model of tauopathies, the NFTs formed by the expression of mutant tau were enhanced by the co-expression of a mutant form of APP (APP695-Swedish, K670N and M671L) or by the injection of Ab42.…”

“…10,11 Parkinson's disease is a common neurodegenerative syndrome characterized by the loss of dopaminergic neurons in the substantia nigra, formation of filamentous intraneuronal inclusions (Lewy bodies), and an extrapyramidal movement disorder. Mutations in the a-synuclein gene are linked to familial Parkinson's disease, and a-synuclein accumulates in Lewy bodies and Lewy neurites.…”