Human Tau isoform-specific presynaptic deficits in a Drosophila Central Nervous System circuit

Kadas, Dimitrios; Papanikolopoulou, Katerina; Xirou, Sophia; Consoulas, Christos; Skoulakis, Efthimios M. C.

doi:10.1016/j.nbd.2018.12.004

Cited by 9 publications

(9 citation statements)

References 46 publications

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“…However, the outcome of the response depends critically on Cys-291, since its absence (mutation or lack of the second MBR in 0N3R) suppressed the Nrf2 signaling, whereas its presence led to activation and upregulation of Nrf2 target genes. Therefore, our collective data strongly support the notion that cysteine-mediated interactions could define isoform-specific differences (3R vs 4R) (Goode et al, 2000;Sealey et al, 2017;Kadas et al, 2019).…”

Section: Discussionsupporting

confidence: 87%

The Two Cysteines of Tau Protein Are Functionally Distinct and Contribute Differentially to Its Pathogenicityin Vivo

Prifti¹,

Tsakiri²,

Vourkou³

et al. 2020

J. Neurosci.

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Although Tau accumulation is clearly linked to pathogenesis in Alzheimer's disease and other Tauopathies, the mechanism that initiates the aggregation of this highly soluble protein in vivo remains largely unanswered. Interestingly, in vitro Tau can be induced to form fibrillar filaments by oxidation of its two cysteine residues, generating an intermolecular disulfide bond that promotes dimerization and fibrillization. The recently solved structures of Tau filaments revealed that the two cysteine residues are not structurally equivalent since Cys-322 is incorporated into the core of the fibril, whereas Cys-291 projects away from the core to form the fuzzy coat. Here, we examined whether mutation of these cysteines to alanine affects differentially Tau mediated toxicity and dysfunction in the well-established Drosophila Tauopathy model. Experiments were conducted with both sexes, or with either sex. Each cysteine residue contributes differentially to Tau stability, phosphorylation status, aggregation propensity, resistance to stress, learning, and memory. Importantly, our work uncovers a critical role of Cys-322 in determining Tau toxicity and dysfunction.

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Section: Discussionsupporting

confidence: 87%

The Two Cysteines of Tau Protein Are Functionally Distinct and Contribute Differentially to Its Pathogenicityin Vivo

Prifti¹,

Tsakiri²,

Vourkou³

et al. 2020

J. Neurosci.

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“…Furthermore, during development at the larval neuromuscular junction, motor neurons overexpressing human 0N3R or 0N4R caused a reduction in size and irregular and abnormally shaped synaptic terminals, a reduction in endocytosis and exocytosis and a reduction in high frequency synaptic transmission (Chee et al, 2005; Zhou et al, 2017). Also, while expression of tau 0N3R in the adult giant fiber system caused increased failure rate at high frequency stimulation, expression of 0N4R caused defects in stimulus conduction, response speed and conduction velocity (Kadas et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Restoration of Olfactory Memory in Drosophila Overexpressing Human Alzheimer’s Disease Associated Tau by Manipulation of L-Type Ca2+ Channels

Higham¹,

Hidalgo

Buhl³

et al. 2019

Front. Cell. Neurosci.

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The cellular underpinnings of memory deficits in Alzheimer’s disease (AD) are poorly understood. We utilized the tractable neural circuits sub-serving memory in Drosophila to investigate the role of impaired Ca2+ handling in memory deficits caused by expression of human 0N4R isoform of tau which is associated with AD. Expression of tau in mushroom body neuropils, or a subset of mushroom body output neurons, led to impaired memory. By using the Ca2+ reporter GCaMP6f, we observed changes in Ca2+ signaling when tau was expressed in these neurons, an effect that could be blocked by the L-type Ca2+ channel antagonist nimodipine or reversed by RNAi knock-down of the L-type channel gene. The L-type Ca2+ channel itself is required for memory formation, however, RNAi knock-down of the L-type Ca2+ channel in neurons overexpressing human tau resulted in flies whose memory is restored to levels equivalent to wild-type. Expression data suggest that Drosophila L-type Ca2+ channel mRNA levels are increased upon tau expression in neurons, thus contributing to the effects observed on memory and intracellular Ca2+ homeostasis. Together, our Ca2+ imaging and memory experiments suggest that expression of the 0N4R isoform of human tau increases the number of L-type Ca2+ channels in the membrane resulting in changes in neuronal excitability that can be ameliorated by RNAi knockdown or pharmacological blockade of L-type Ca2+ channels. This highlights a role for L-type Ca2+ channels in tauopathy and their potential as a therapeutic target for AD.

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“…Similarly, neuronal tauopathy models have demonstrated that different tau isoforms yield differential toxicity during development and in the adult. For example, 0N3R tau is particularly toxic to larval neurons [55], while 0N4R more readily promotes neurodegeneration and impairs learning and memory in the adult [55,56], perhaps the result of tau isoform-specific effects on synaptic transmission at adult CNS synapses[57]. Here, we characterize the pathological effects of glial expression of 0N4R tau, but given the isoform-specific effects of tau on neuronal physiology, an interrogation into tau isoform effects on glial cells is warranted.…”

Section: Discussionmentioning

confidence: 99%

Developmental expression of human tau in Drosophila melanogaster glial cells induces motor deficits and disrupts maintenance of PNS axonal integrity, without affecting synapse formation

et al. 2019

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Tauopathies are a class of neurodegenerative diseases characterized by the abnormal phosphorylation and accumulation of the microtubule-associated protein, tau, in both neuronal and glial cells. Though tau pathology in glial cells is a prominent feature of many of these disorders, the pathological contribution of these lesions to tauopathy pathogenesis remains largely unknown. Moreover, while tau pathology is predominantly found in the central nervous system, a role for tau in the cells of the peripheral nervous system has been described, though not well characterized. To investigate the effects of glial tau expression on the development and maintenance of the peripheral nervous system, we utilized a Drosophila melanogaster model of tauopathy that expresses human wild-type tau in glial cells during development. We found that glial tau expression during development results in larval locomotor deficits and organismal lethality at the pupal stage, without affecting larval neuromuscular junction synapse development or post-synaptic amplitude. There was, however, a significant decrease in the decay time of synaptic potentials upon repeated stimulation of the motoneuron. Behavioral abnormalities were accompanied by glial cell death, disrupted maintenance of glial-axonal integrity, and the abnormal accumulation of the presynaptic protein, Bruchpilot, in peripheral nerve axons. Together, these data demonstrate that human tau expression in Drosophila glial cells does not affect neuromuscular junction synapse formation during development, but is deleterious to the maintenance of glial-axonal interactions in the peripheral nervous system.

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Human Tau isoform-specific presynaptic deficits in a Drosophila Central Nervous System circuit

Cited by 9 publications

References 46 publications

The Two Cysteines of Tau Protein Are Functionally Distinct and Contribute Differentially to Its Pathogenicityin Vivo

The Two Cysteines of Tau Protein Are Functionally Distinct and Contribute Differentially to Its Pathogenicityin Vivo

Restoration of Olfactory Memory in Drosophila Overexpressing Human Alzheimer’s Disease Associated Tau by Manipulation of L-Type Ca2+ Channels

Developmental expression of human tau in Drosophila melanogaster glial cells induces motor deficits and disrupts maintenance of PNS axonal integrity, without affecting synapse formation

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