Differential Effects of Human Tau Isoforms to Neuronal Dysfunction and Toxicity in the Drosophila CNS

Abstract

Accumulation of highly post-translationally modified tau proteins is a hallmark of neurodegenerative disorders known as tauopathies, the most common of which is Alzheimer’s disease. Although six tau isoforms are found in the human brain, the majority of animal and cellular tauopathy models utilize a representative single isoform. However, the six human tau isoforms present overlapping but distinct distributions in the brain and are differentially involved in particular tauopathies. These observations support the notion that tau isoforms possess distinct functional properties important for both physiology and pathology. To address this hypothesis, the six human brain tau isoforms were expressed singly in the Drosophila brain and their effects in an established battery of assays measuring neuronal dysfunction, vulnerability to oxidative stress and life span were systematically assessed comparatively. The results reveal isoform-specific effects clearly not attributed to differences in expression levels but correlated with the number of microtubule-binding repeats and the accumulation of a particular isoform in support of the functional differentiation of these tau isoforms. Delineation of isoform-specific effects is essential to understand the apparent differential involvement of each tau isoform in tauopathies and their contribution to neuronal dysfunction and toxicity.

The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

“…Furthermore, a comprehensive study performed in flies characterized the effect of individual human TAU isoform overexpression and demonstrated that overall lifespan is affected equally by all isoforms. Interestingly, specifically 4R TAU isoforms (0N, 1N, and 2N) lead to significant learning and memory deficits, that were not observed in 3R expressing animals 306 . TAU has been shown to interact with RNPs and ribosomal subunits (reviewed in 142 ), and TAU oligomers formed by 1N4R induce a translational stress response and inhibit translation, resulting in stress granule formation and changes of dendrite length and morphology that further drive neuronal dysfunction in primary murine neurons 163,170,307,308 .…”

“…Interestingly, specifically 4R TAU isoforms (0N, 1N, and 2N) lead to significant learning and memory deficits, that were not observed in 3R expressing animals. 306 TAU has been shown to interact with RNPs and ribosomal subunits (reviewed in 142 ), and TAU oligomers formed by 1N4R induce a translational stress response and inhibit translation, resulting in stress granule formation and changes of dendrite length and morphology that further drive neuronal dysfunction in primary murine neurons. 163 , 170 , 307 , 308 Besides the likely contribution of the N‐terminal inserts to disease pathology, the presence of an additional repeat domain has been shown to enhance the aggregation propensity of TAU isoforms in vitro.…”