Tau-mediated axonal degeneration is prevented by activation of the WldS pathway.

Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of WldS. In a Drosophila model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, WldS was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit OR47b was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.

Curcumin as a Holistic Treatment for Tau Pathology.

Global forecasts for prevalence of Alzheimer's Disease (AD) estimate that 152.8 million people will have dementia in 2050, a sharp rise from 57.4 million in 2019 (GBD 2019). This rise can be attributable to increases in population growth and aging, but in the absence of disease-modifying therapies it poses a huge societal challenge that must be addressed urgently. One way to combat this challenge is to explore the utility of holistic treatments that may protect against AD, including traditional herbs, spices and other nutraceuticals that are pharmacologically safe, inexpensive and readily available. In this light, the spice turmeric, and its active ingredient curcumin, has been investigated as a potential holistic treatment for AD over the past 2 decades; however, promising results with animal studies have not translated to success in clinical trials. One issue is that most animal models examining the effects of curcumin and curcumin derivatives in AD have been done with a focus at ameliorating amyloid pathology. Due to the limited success of Amyloid-ß-based drugs in recent clinical trials, tau-focused therapeutics provide a promising alternative. In this article, we aim to provide a clearer picture of what is currently known about the effectiveness of curcumin and curcumin derivatives to ameliorate tau pathology. Tau focused studies may help inform more successful clinical studies by placing greater emphasis on the development and optimised delivery of curcumin derivatives that more effectively target tau pathology.

An evaluation of Drosophila as a model system for studying tauopathies such as Alzheimer's disease.

Work spanning almost two decades using the fruit fly, Drosophila melanogaster, to study tau-mediated neurodegeneration has provided valuable and novel insights into the causes and mechanisms of tau-mediated toxicity and dysfunction in tauopathies such as Alzheimer's disease (AD). The fly has proven to be an excellent model for human diseases because of its cost efficiency, and the availability of powerful genetic tools for use in a comparatively less-complicated, but evolutionarily conserved, in vivo system. In this review, we provide a critical evaluation of the insights provided by fly models, highlighting both the advantages and limitations of the system. The fly has contributed to a greater understanding of the causes of tau abnormalities, the role of these abnormalities in mediating toxicity and/or dysfunction, and the nature of causative species mediating tau-toxicity. However, it is not possible to perfectly model all aspects of human degenerative diseases. What sets the fly apart from other animal models is its genetic tractability, which makes it highly amenable to overcoming experimental limitations. The explosion of genetic technology since the first fly disease models were established has translated into fly lines that allow for greater temporal control in restricting tau expression to single neuron types, and lines that can label and monitor the function of subcellular structures and components; thus, fly models offer an unprecedented view of the neurodegenerative process. Emerging genetic technology means that the fly provides an ever-evolving experimental platform for studying disease.

Current techniques for high-resolution mapping of behavioral circuits in Drosophila.

Understanding behavior requires unraveling the mysteries of neurons, glia, and their extensive connectivity. Drosophila has emerged as an excellent organism for studying the neural basis of behavior. This can be largely attributed to the extensive effort of the fly community to develop numerous sophisticated genetic tools for visualizing, mapping, and manipulating behavioral circuits. Here, we attempt to highlight some of the new reagents, techniques and approaches available for dissecting behavioral circuits in Drosophila. We focus on detailing intersectional strategies such as the Flippase-induced intersectional Gal80/Gal4 repression (FINGR), because of the tremendous potential they possess for mapping the minimal number of cells required for a particular behavior. The logic and strategies outlined in this review should have broad applications for other genetic model organisms.

Differential pleiotropy and HOX functional organization.

Key studies led to the idea that transcription factors are composed of defined modular protein motifs or domains, each with separable, unique function. During evolution, the recombination of these modular domains could give rise to transcription factors with new properties, as has been shown using recombinant molecules. This archetypic, modular view of transcription factor organization is based on the analyses of a few transcription factors such as GAL4, which may represent extreme exemplars rather than an archetype or the norm. Recent work with a set of Homeotic selector (HOX) proteins has revealed differential pleiotropy: the observation that highly-conserved HOX protein motifs and domains make small, additive, tissue specific contributions to HOX activity. Many of these differentially pleiotropic HOX motifs may represent plastic sequence elements called short linear motifs (SLiMs). The coupling of differential pleiotropy with SLiMs, suggests that protein sequence changes in HOX transcription factors may have had a greater impact on morphological diversity during evolution than previously believed. Furthermore, differential pleiotropy may be the genetic consequence of an ensemble nature of HOX transcription factor allostery, where HOX proteins exist as an ensemble of states with the capacity to integrate an extensive array of developmental information. Given a new structural model for HOX functional domain organization, the properties of the archetypic TF may require reassessment.

Acquisition of a leucine zipper motif as a mechanism of antimorphy for an allele of the Drosophila Hox gene Sex combs reduced.

In 1932, Müller first used the term "antimorphic" to describe mutant alleles that have an effect that is antagonistic to that of the wild-type allele from which they were derived. In a previous characterization of mutant alleles of the Drosophila melanogaster Hox gene, Sex combs reduced (Scr), we identified the missense, antimorphic allele Scr(14), which is a Ser10-to-Leu change in the N-terminally located, bilateran-specific octapeptide motif. Here we propose that the cause of Scr(14) antimorphy is the acquisition of a leucine zipper oligomerization motif spanning the octapeptide motif and adjacently located protostome-specific LASCY motif. Analysis of the primary and predicted secondary structures of the SCR N-terminus suggests that while the SCR(+) encodes a short, α-helical region containing one putative heptad repeat, the same region in SCR(14) encodes a longer, α-helical region containing two putative heptad repeats. In addition, in vitro cross-linking assays demonstrated strong oligomerization of SCR(14) but not SCR(+). For in vivo sex comb formation, we observed reciprocal inhibition of endogenous SCR(+) and SCR(14) activity by ectopic expression of truncated SCR(14) and SCR(+) peptides, respectively. The acquisition of an oligomerization domain in SCR(14) presents a novel mechanism of antimorphy relative to the dominant negative mechanism, which maintains oligomerization between the wild-type and mutant protein subunits.

Developmental competence and the induction of ectopic proboscises in Drosophila melanogaster.

Developmental competence is the response of a cell(s) to information. Determination of adult labial identity in Drosophila requires Proboscipedia (PB) and Sex combs reduced (SCR); however, co-ectopic expression of PB and SCR is not sufficient for induction of ectopic adult labial identity, because the developmental information supplied by PB and SCR is suppressed. The evolutionarily conserved LASCY, DYTQL, NANGE motifs, and the C-terminal domain of SCR are sequence elements that mediate some, or all, of the suppression of ectopic proboscis determination. Therefore, the developmentally competent primordial proboscis cells provide an environment devoid of suppression, allowing PB and SCR to determine proboscis identity. SCR derivatives lacking suppression sequences weakly induce ectopic proboscis transformations independently of PB, suggesting that SCR may be the activity required for induction of adult labial identity, as is the case for larval labial identity. A possible explanation for PB independence of SCR in determination of adult and embryonic labial identity is PB operates as a competence factor that switches SCR from determining T1 identity to labial identity during metamorphosis. Lastly, labial determination is not conserved between SCR and murine HOXA5, suggesting that SCR has acquired this activity during evolution.

Analysis of the sequence and phenotype of Drosophila Sex combs reduced alleles reveals potential functions of conserved protein motifs of the Sex combs reduced protein.

The Drosophila Hox gene, Sex combs reduced (Scr), is required for patterning the larval and adult, labial and prothoracic segments. Fifteen Scr alleles were sequenced and the phenotypes analyzed in detail. Six null alleles were nonsense mutations (Scr(2), Scr(4), Scr(11), Scr(13), Scr(13A), and Scr(16)) and one was an intragenic deletion (Scr(17)). Five hypomorphic alleles were missense mutations (Scr(1), Scr(3), Scr(5), Scr(6), and Scr(8)) and one was a small protein deletion (Scr(15)). Protein sequence changes were found in four of the five highly conserved domains of SCR: the DYTQL motif (Scr(15)), YPWM motif (Scr(3)), Homeodomain (Scr(1)), and C-terminal domain (CTD) (Scr(6)), indicating importance for SCR function. Analysis of the pleiotropy of viable Scr alleles for the formation of pseudotracheae suggests that the DYTQL motif and the CTD mediate a genetic interaction with proboscipedia. One allele Scr(14), a missense allele in the conserved octapeptide, was an antimorphic allele that exhibited three interesting genetic properties. First, Scr(14)/Df had the same phenotype as Scr(+)/Df. Second, the ability of the Scr(14) allele to interact intragenetically with Scr alleles mapped to the first 82 amino acids of SCR, which contains the octapeptide motif. Third, Scr(6), which has two missense changes in the CTD, did not interact genetically with Scr(14).