PubMed: 29191965

<i>Caenorhabditis elegans</i> models of tauopathy.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Choudhary B | Mandelkow E | Pir GJ

Evidence c1803ce402

In a recent study, tau was reported to impair neurotransmission at the presynapse by binding and inhibiting synaptic vesicle transport and release, an effect mediated by the N-terminal domain (78).

Evidence 4ef59d9a5c

For example, Fatouros et al. (68) tested several tau-aggregation inhibitor compounds such as methylene blue, a rhodanine derivative (bb14), and a phenylthiazolyl hydrazide derivative (BSc3094), which reduce the insoluble tau and partially suppress the Unc phenotype.

Evidence 0fe5514086

The antipsychotic drug azaperone shows neuroprotective effects, improves locomotion, reduces the insoluble tau, and partially abates the neurodegeneration in this tauopathy model (104).

Evidence ebb3e6e366

Tau lines described by Miyasaka et al. show tau accumulations predominantly in the cell bodies as seen by immunostaining (62).

Evidence 8223d0563d

Tien et al. (50) showed a physical interaction of PTL-1 with Kinesin-3/UNC-104, a major motor for synaptic vesicle proteins and dense core vesicles in C. elegans.

Evidence 28bba4dec4

One exception is the report of the accumulation of tau aggregates in presynaptic boutons in transgenic mice, whereby it induces synaptic dysfunction and loss of presynapses (77).

Evidence 613a5e0ef7

Nonetheless, it is assumed that tau aggregation may be driven by phosphorylation at certain sites (95), whereas phosphorylation at other sites may inhibit aggregation (96).

Evidence 7164bcc393

Indeed, evidence from both human and mouse studies indicates that soluble oligomers rather than insoluble aggregates are toxic to normal neurons (70).

Evidence 7a7c546678

Another compound of the ATPZ class also is protective and partially ameliorates the neurodegeneration in this tauopathy model.

Evidence cf09c7044d

Indeed, aggresome formation represents one such process employed by a cell to discard misfolded proteins (125) and has been implicated in neurodegenerative diseases (126).

Evidence 094c245d15

Thus, TauA152T affects both neuronal aging and whole organism lifespan

Evidence 45c5a063ee

A recent study, Krieg et al. (49), established the role of PTL-1 in the maintenance and repair of the microtubule cytoskeleton after transient damage induced by mechanical stress. This process requires other microtubule-associated proteins such as b-spectrin.

Evidence 64741ee2f7

In a recent study, the antiepileptic drug ethosuximide increased the lifespan and partially corrected the Unc phenotype in TauV337M worms with the effect dependent on the insulin signaling pathway (106).

Evidence e2a963f850

Three transgenic lines were generated based on 1N4R wild-type MAPT or its FTD-17 mutant variants P301L and V337M. The mutant lines showed a stronger Unc phenotype than the wild-type tau lines and the severity of the Unc phenotype progressed with age

Evidence 4647e7a719

Genetic interaction studies involving ptl-1 and mutants in other genes associated with microtubules such as mec-12 (a-tubulin) and mec-7 (btubulin), suggested a larger functional role of PTL-1 in mechanosensation (45).

Evidence fb509b44c9

A study from the same group whereby the knockdown of dynamin binding protein (DNMBP/TUBA), a known interactor of UNC-34 (120), elevated the toxicity induced by TauV337M(80), lends further support to this notion

Evidence b50f066a40

This worm also shows reduced survival, accumulates detergent-insoluble tau, and undergoes late-onset neurodegeneration (66)

Evidence f980d26d0f

For example, the first transgenic C. elegans human disease model was based on the expression of the AD-associated Ab peptide in body wall muscles, resulting in paralysis that could be suppressed by coexpression of transthyretin (29).

Evidence 0968c0bbb2

As a result, the proaggregant lines showed a range of defects including paralysis, axonal degeneration of GABAergic and cholinergic motor neurons, presynaptic defects, synapse loss, and mitochondrial transport defects early in adulthood

Evidence e2564110e3

Similarly, elimination of CDK-5 improved the touch response in the mutant TauR406W-line, but failed to improve it inother line

Evidence a3555b4ae4

Frontotemporal dementia with parkinsonism–mutant tau expression (0N4R-tau P301L and 0N4R-tau R406W), on the other hand, resulted in a reduced touch response that worsened with age

Evidence 95861dccca

At the later stages, the mutant-tau lines showed microtubule loss and non-apoptotic neuronal death, paralleled by a complete loss of touch response (62).

Evidence d74fa60b30

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91).

Evidence 7aee0eb2ba

Indeed, 2 of the candidates identified in an RNAi screen that worsened the Unc phenotype in the TauV337M worm, called enhancers of tauopathy, were postsynaptic (80).

Evidence 7d82ad2094

AEX-1, predominantly expressed in muscles and intestine, regulates the retrograde signaling at neuromuscular junctions and is required for the normal localization of synaptic vesicle fusion protein UNC-13

Evidence fd4a40f18b

acr-14 controls body movement by modulating the synaptic inputs and outputs of the ventral cord neural circuitry (83).

Evidence c3b6eb7f71

AD brains show an upregulation of CHRNA7 (acr-14 homolog in humans) (84), where it may mediate the Ab-induced tau pathology (85).

Evidence 26d4035509

Some of these enhancer genes are specific only to the tau-induced disease phenotype and include genes encoding proteins like WNT2 (111), TTBK2 (112), GSK-3b (113), TAOK1 (114, 115), CTSE (116) and CHRNA7 (117), have been implicated in tau-mediated pathology.

Evidence 119b8d1617

Loss of bas-1 function improved the motor function, reduced insoluble tau and its phosphorylation and ameliorated the tau-induced neurodegeneration without increasing the longevity in TauV337M worms

Evidence 4e2d6a6515

A recent addition to the suppressors of tau-induced toxicity in C. elegans is the bas-1 gene (105), encoding the dopa decarboxylase, loss of which reduces the dopamine and serotonin levels (128–130).

Evidence 71cb6011fa

Loss of function in other genes (cat-2, cat-4, tph-1) that also regulate the dopamine or serotonin levels (130–132),did not affect the tau-induced toxicity in TauV337M; however, their activity is essential for bas-1-mediated suppression of tau-induced toxicity in TauV337M (105)

Evidence 6ce331757d

Eliminating sut-2 resulted in partial recovery of Unc phenotype, less neurodegeneration and reduction of insoluble tau in the TauV337M worm; whereas sut-2 overexpression exacerbated the pathology

Evidence 1beeb02876

Homologs of SUT-2 exist in higher animals, including humans (MSUT-2), and reducing the MSUT-2 levels was found to be protective against tau-induced toxicity in a cell model (121).

Evidence 43cc35eb44

Although a direct mechanism by which SUT-2 acts is not known, functional evidence of its binding partner ZYG-12 (122) suggests that it may act via modulating the aggresome formation by ZYG-12 (123,124).

Evidence 7b3fbf00ee

Comparison of the mitochondrial transport in the wildtype tau and TauA152T lines revealed striking differences; wild-type tau lines showed a late onset akin to both antero- and retrograde mitochondrial transport defects, whereas TauA152T lines showed mainly early-onset anterograde mitochondrial transport defects

Evidence 662e292eab

Although the wild-type tau lines showed a mild late-onset dose-dependent Unc phenotype, TauA152T worms showed early-onset paralysis and acute neuronal dysfunction.

Evidence 588be2f99d

The transgenic lines exhibited a progressive age-associated Unc phenotype, with or without phospho-mimicking mutations

Evidence 3167744a29

Only PHP tau expression induced morphologic abnormalities in the motor neurons, but none of the lines developed substantial neurodegeneration

Evidence b2f0fae43f

Phosphorylation is generally increased in AD and can be recognized by diagnostic antibodies against phosphoepitopes

Evidence dadb4b85ad

For example, AD brain tau is;4-fold more phosphorylated than normal adult brain tau(93), but a high state of phosphorylation can also occur physiologically (e.g., in fetal brain or in hibernating animals (94).

Evidence 78d5572d2c

For example, both soluble and insoluble tau from transgenic worms generated by Kraemer and colleagues (66) was phosphorylated at most of the sites examined; however, the insoluble tau did not show reactivity at the AT8 and pS422 epitopes, which are pronounced in human AD tau.

Evidence 53a9327c01

Another MAPT polymorphism (A152T) was recently identified in patients diagnosed with progressive supranuclear palsy (PSP) (72–74).

Evidence 981e500ab8

Dephosphorylation of tau is achieved mainly by protein phosphatase (PP)2A, PP2B (calcineurin), and PP-1 (92).


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