Olfactory Learning Deficits in Mutants for leonardo, a Drosophila Gene Encoding a 14-3-3 Protein

AbstractStudies of Drosophila and other insects have indicated an essential role for the mushroom bodies in learning and memory. The leonardo gene encodes a Drosophila protein highly homologous to the vertebrate 14-3-3ζ isoform, a protein well studied for biochemical roles but without a well established biological function. The gene is expressed abundantly and preferentially in mushroom body neurons. Mutant alleles that reduce LEONARDO protein levels in the mushroom bodies significantly decrease the capacity for olfactory learning, but do not affect sensory modalities or brain neuroanatomy that are requisite for conditioning. These results establish a biological role for 14-3-3 proteins in mushroom body–mediated learning and memory processes, and suggest that proteins known to interact with them, such as RAF-1 or other protein kinases, may also have this biological function

A third functional isoform enriched in mushroom body neurons is encoded by the Drosophila 14-3-3ζ gene

Abstract14-3-3 Proteins are highly conserved across eukaryotes, typically encoded by multiple genes in most species. Drosophila has only two such genes, 14-3-3ζ (leo), encoding two isoforms LEOI and LEOII, and 14-3-3ε. We report a bona fide third functional isoform encoded by leo divergent from the other two in structurally and functionally significant areas, thus increasing 14-3-3 diversity in Drosophila. Furthermore, we used a novel approach of spatially restricted leo abrogation by RNA-interference and revealed differential LEO distribution in adult heads, with LEOIII enrichment in neurons essential for learning and memory in Drosophila

Interaction of Akt-Phosphorylated Ataxin-1 with 14-3-3 Mediates Neurodegeneration in Spinocerebellar Ataxia Type 1

AbstractSpinocerebellar ataxia type 1 (SCA1) is one of several neurological disorders caused by a CAG repeat expansion. In SCA1, this expansion produces an abnormally long polyglutamine tract in the protein ataxin-1. Mutant polyglutamine proteins accumulate in neurons, inducing neurodegeneration, but the mechanism underlying this accumulation has been unclear. We have discovered that the 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. The association of ataxin-1 with 14-3-3 is regulated by Akt phosphorylation, and in a Drosophila model of SCA1, both 14-3-3 and Akt modulate neurodegeneration. Our finding that phosphatidylinositol 3-kinase/Akt signaling and 14-3-3 cooperate to modulate the neurotoxicity of ataxin-1 provides insight into SCA1 pathogenesis and identifies potential targets for therapeutic intervention

Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy.

Tau exists as six closely related protein isoforms in the adult human brain. These are generated from alternative splicing of a single mRNA transcript and they differ in the absence or presence of two N-terminal and three or four microtubule binding domains. Typically all six isoforms have been considered functionally similar. However, their differential involvement in particular tauopathies raises the possibility that there may be isoform-specific differences in physiological function and pathological role. To explore this, we have compared the phenotypes induced by the 0N3R and 0N4R isoforms in Drosophila. Expression of the 3R isoform causes more profound axonal transport defects and locomotor impairments, culminating in a shorter lifespan than the 4R isoform. In contrast, the 4R isoform leads to greater neurodegeneration and impairments in learning and memory. Furthermore, the phosphorylation patterns of the two isoforms are distinct, as is their ability to induce oxidative stress. These differences are not consequent to different expression levels and are suggestive of bona fide physiological differences in isoform biology and pathological potential. They may therefore explain isoform-specific mechanisms of tau-toxicity and the differential susceptibility of brain regions to different tauopathies

A European network to fine-tune the proteome

Publisher Copyright: © 2024 The Author(s)Proteins are essential molecular actors in every cellular process. From their synthesis to their degradation, they are subject to continuous quality control mechanisms to ensure that they fulfil cellular needs in proper and timely fashion. Proteostasis is a key process allowing cells or organisms to maintain an appropriate but dynamic equilibrium of their proteome (the ensemble of all their proteins). It relies on multiple mechanisms that together control the level, fate and function of individual proteins, and ensure elimination of abnormal ones. The proteostasis network is essential for development and adaptation to environmental changes or challenges. Its dysfunctions can lead to accumulation of deleterious proteins or, conversely, to excessive degradation of beneficial ones, and are implicated in many diseases such as cancers, neurodegeneration, or developmental and aging disorders. Manipulating this network to control abundance of selected target proteins is therefore a strategy with enormous therapeutic or biotechnological potential. The ProteoCure COST Action gathers more than 350 researchers and their teams (31 countries represented) from the academic, clinical, and industrial sectors, who share the conviction that our understanding of proteostasis is mature enough to develop novel and highly specific therapies based on selective tuning of protein levels. Towards this objective, the Action organizes community-building activities to foster synergies among its participants and reinforce training of the next generation of European researchers. Its ambition is to function as a knowledge-based network and a creative exchange hub on normal and pathologic proteostasis, focusing on developing innovative tools modulating the level of specific protein(s).publishersversioninpres

Cell type-specific processing of human Tau proteins in Drosophila

AbstractAccumulation of hyperphosphorylated Tau is associated with a number of neurodegenerative diseases collectively known as tauopathies. Differences in clinical and cognitive profiles among them suggest differential sensitivity of neuronal populations to Tau levels, phosphorylation and mutations. We used tissue specific expression of wild type and mutant human tau transgenes to demonstrate differential phosphorylation and stability in a cell type-specific manner, which includes different neuronal types and does not correlate with the level of accumulated protein. Rather, they likely reflect the spatial distribution or regulation of Tau-targeting kinases and phosphatases

Protection from premature habituation requires functional mushroom bodies in Drosophila

Diminished responses to stimuli defined as habituation can serve as a gating mechanism for repetitive environmental cues with little predictive value and importance. We demonstrate that wild-type animals diminish their responses to electric shock stimuli with properties characteristic of short- and long-term habituation. We used spatially restricted abrogation of neurotransmission to identify brain areas involved in this behavioral response. We find that the mushroom bodies and, in particular, the α/β lobes appear to guard against habituating prematurely to repetitive electric shock stimuli. In addition to protection from premature habituation, the mushroom bodies are essential for spontaneous recovery and dishabituation. These results reveal a novel modulatory role of the mushroom bodies on responses to repetitive stimuli in agreement with and complementary to their established roles in olfactory learning and memory

Human Tau aggregates are permissive to protein synthesis-dependent memory in Drosophila tauopathy models

Tauopathies including Alzheimer's disease, are characterized by progressive cognitive decline, neurodegeneration, and intraneuronal aggregates comprised largely of the axonal protein Tau. It has been unclear whether cognitive deficits are a consequence of aggregate accumulation thought to compromise neuronal health and eventually lead to neurodegeneration. We use the Drosophila tauopathy model and mixed-sex populations to reveal an adult onset pan-neuronal Tau accumulation-dependent decline in learning efficacy and a specific defect in protein synthesis-dependent memory (PSD-M), but not in its protein synthesis-independent variant. We demonstrate that these neuroplasticity defects are reversible on suppression of new transgenic human Tau expression and surprisingly correlate with an increase in Tau aggregates. Inhibition of aggregate formation via acute oral administration of methylene blue results in re-emergence of deficient memory in animals with suppressed human Tau (hTau) 0N4R expression. Significantly, aggregate inhibition results in PSD-M deficits in hTau 0N3R-expressing animals, which present elevated aggregates and normal memory if untreated with methylene blue. Moreover, methylene blue-dependent hTau 0N4R aggregate suppression within adult mushroom body neurons also resulted in emergence of memory deficits. Therefore, deficient PSD-M on human Tau expression in the Drosophila CNS is not a consequence of toxicity and neuronal loss because it is reversible. Furthermore, PSD-M deficits do not result from aggregate accumulation, which appears permissive, if not protective of processes underlying this memory variant. SIGNIFICANCE STATEMENT Intraneuronal Tau aggregate accumulation has been proposed to underlie the cognitive decline and eventual neurotoxicity that characterizes the neurodegenerative dementias known as tauopathies. However, we show in three experimental settings that Tau aggregates in the Drosophila CNS do not impair but rather appear to facilitate processes underlying protein synthesis-dependent memory within affected neurons. </p