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PubMed: 22611162

Title
Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity.
Journal
Human molecular genetics
Volume
21
Issue
None
Pages
3587-603
Date
2012-08-15
Authors
Baumeister R | Biernat J | Fatouros C | Koushika SP | Mandelkow E | Mandelkow EM | Pir GJ | Schmidt E

Evidence 51af0efa73
JSON

Overall, Tau, both in the soluble and in the insoluble fractions, was phosphorylated to a higher degree in the pro-aggregant strain compared with the other two strains.

p(HGNC:MAPT, var("p.Lys280del")) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Evidence a8ee67c9f0
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We supplemented the growth medium of syn- chronized L1 larvae (pro-aggregant strain) with 25 m M MB and measured their locomotion speed as day 1 young adults. This treatment led to 15% amelioration of locomotion (Sup- plementary Material, Fig. S6A).

a(CHEBI:"methylene blue") increases bp(GO:locomotion) View Subject | View Object

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Annotations
MeSH
Tauopathies

Evidence 3965789e6f
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At the biochemical level, MB treatment altered Tau solubility, shifting the equilibrium towards more soluble Tau and reduced detergent-insoluble Tau by  35% in the pro-aggregant strain (Fig. 8A, quantitation in 8B), con- sistent with its anti-aggregation properties (31).

a(CHEBI:"methylene blue") decreases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence afafc7dbfd
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For this purpose, we focused on the well-characterized DK280 mutation (10–13), which specifically leads to aggregation-mediated toxicity.

a(HBP:"Tau aggregates") increases path(HBP:proteotoxicity) View Subject | View Object

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p(HGNC:MAPT, var("p.Lys280del")) increases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence 06a2453b26
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Aberrant phosphorylation and aggregation of Tau have been linked to axonal transport problems, synaptic malfunction and degeneration (6).

a(HBP:"Tau aggregates") decreases bp(GO:"axonal transport") View Subject | View Object

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a(HBP:"Tau aggregates") decreases bp(GO:"synaptic signaling") View Subject | View Object

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a(HBP:"Tau aggregates") decreases bp(GO:"maintenance of synapse structure") View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases bp(GO:"axonal transport") View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases bp(GO:"synaptic signaling") View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases bp(GO:"maintenance of synapse structure") View Subject | View Object

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Evidence 38bc578cc2
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Resistance to aldicarb can arise from either a pre- or a post-synaptic perturbation, whereas resistance to levamisole typically indicates a post-synaptic defect (50). Animals of the pro-aggregant strain displayed a mild resist- ance to aldicarb, producing a paralysis profile intermediate between the sensitive wild-type N2 and the resistant rab-3(js49) strain, which we used as controls (Fig. 5A).

a(HBP:"Tau aggregates") decreases bp(GO:"synaptic signaling") View Subject | View Object

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Evidence 9d8edb20d9
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This indicated that SNB-1 failed to properly accumulate at the presynaptic termini of young adult pro-aggregant worms.

a(HBP:"Tau aggregates") decreases p(UNIPROT:O02495) View Subject | View Object

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Annotations
MeSH
Presynaptic Terminals
MeSH
Neurons

Evidence d3a3e3d6f0
JSON

We crossed WyEx2709 into the pro-aggregant strain (resulting in strain BR6011) and discov- ered that this regular mitochondrial distribution was distorted.

a(HBP:"Tau aggregates") decreases bp(GO:"intracellular distribution of mitochondria") View Subject | View Object

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Evidence 98adac4485
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The velocity of mitochondrial transport in the pro-aggregant strain was lower than in wild-type (mean + SD ¼ 171 + 111 versus 256 + 117 nm/s), whereas the anti-aggregant strain (194 + 131 nm/ s) did not substantially differ from wild- type (Fig. 7D).

a(HBP:"Tau aggregates") decreases bp(GO:"axonal transport of mitochondrion") View Subject | View Object

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Evidence 8969f6b8b5
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We then applied, in the 96-well liquid culture format, the two most promising hit compounds obtained in a mammalian cell model of Tau toxicity (57), namely the phenylthiazolyl- hydrazide derivatives Bsc3094 and bb14, and observed a similar amelioration effect in locomotion (Supplementary Ma- terial, Fig. S6B).

a(HBP:bb14) increases bp(GO:locomotion) View Subject | View Object

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Annotations
MeSH
Tauopathies

a(PUBCHEM:25096749) increases bp(GO:locomotion) View Subject | View Object

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Annotations
MeSH
Tauopathies

Evidence 9c15c8b269
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We next analysed the most prominent Tau aggregation inhibitor compound from a recent- ly published in vitro screen (compound #16 in reference 33), which belongs to the ATPZ class of Tau inhibitors (5-amino-3-(4-chlorophenyl)-N-cyclopropyl-4-oxo-3,4-dihyd- rothieno[3,4- D ]pyridazine-1-carboxamide, referred to as cmp16 for simplicity, structure shown in Fig. 9A). This com- pound prevents Tau fibril formation in vitro, and is able to cross the mammalian blood–brain barrier, an attribute that makes it favourable for clinical applications (33).

a(HBP:cmp16) decreases a(HBP:"Tau fibrils") View Subject | View Object

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Evidence 512a95e88b
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At 100 m M , we observed improved locomotion of treated animals. These animals moved approximately 1.6 times faster than DMSO-treated controls (Fig. 9A).

a(HBP:cmp16) increases bp(GO:locomotion) View Subject | View Object

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Evidence 108110a815
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Treatment with cmp16 diminished the progressive accumulation of neurite gaps in the motor neurons of the pro-aggregant animals compared with the DMSO-treated controls (from 3.2 + 1 gaps at day 5 of the DMSO-treated strains to 2.4 + 1 gaps of the cmp16-treated strains, P , 0.05) (Fig. 9B). Lower accumulation of structural damage in neurons can be interpreted as a sign of reduced neu- rodegeneration (22,58).

a(HBP:cmp16) decreases bp(HP:Neurodegeneration) View Subject | View Object

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Annotations
Cell Ontology (CL)
motor neuron
MeSH
Tauopathies

Evidence 4d5dfe0690
JSON

BSc3094 resulted in 40% decrease in the detergent-insoluble Tau (FA fraction) in pro-aggregant animals,

a(PUBCHEM:25096749) decreases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence 113063f9b8
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In one set of C. elegans strains, we expressed the pathological FDTP-17 mutant DK280, which enhances aggregation, whereas the other set harbours, in addition to DK280, the proline substitutions I277P and I308P (PP), which act as b-sheet breakers and prevent aggregation (15).

p(HGNC:MAPT, var("p.Ile277Pro")) decreases a(HBP:"Tau aggregates") View Subject | View Object

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p(HGNC:MAPT, var("p.Ile308Pro")) decreases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence c6e261cbb8
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The motility of the pro-aggregant worms was considerably enhanced upon apply- ing RNAi against F3DK280 (speed ¼ 70.7 + 17 mm/s for RNAi-treated versus 40.3 + 17 for control), whereas the anti- aggregant worms showed no difference upon treatment (Sup- plementary Material, Fig. S1C).

p(HGNC:MAPT, var("p.Lys280del")) decreases bp(GO:locomotion) View Subject | View Object

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Evidence 73ecca8f02
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In contrast, we observed severe developmental defects in the pro-aggregant strain (BR5707) that manifest as increased numbers of persist- ent gaps in both the ventral and dorsal neural cords (mean + SD ¼ 2.7 + 1.4 gaps at the L3 stage).

p(HGNC:MAPT, var("p.Lys280del")) decreases bp(GO:"dorsal spinal cord development") View Subject | View Object

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Annotations
Cell Ontology (CL)
GABAergic neuron

p(HGNC:MAPT, var("p.Lys280del")) decreases bp(GO:"ventral spinal cord development") View Subject | View Object

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Annotations
Cell Ontology (CL)
GABAergic neuron

Evidence b95a7ff359
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In contrast, the pro-aggregant strain showed frequent occurrence of gaps (27.8 + 4.8% of day 1 adult animals), similar to those observed in the GABAergic neurons (Fig. 3E and Supplementary Material, Fig. S3).

p(HGNC:MAPT, var("p.Lys280del")) decreases bp(GO:"dorsal spinal cord development") View Subject | View Object

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Annotations
Cell Ontology (CL)
cholinergic neuron

p(HGNC:MAPT, var("p.Lys280del")) decreases bp(GO:"ventral spinal cord development") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
cholinergic neuron

Evidence cdd4e637d5
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From these data, we conclude that the continued expression of FL Tau V337M and F3DK280 is toxic for the neurons and as a conse- quence, the development of the nervous system is perturbed.

p(HGNC:MAPT, var("p.Lys280del")) increases path(HBP:neurotoxicity) View Subject | View Object

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p(HGNC:MAPT, var("p.Lys280del")) decreases bp(GO:"nervous system development") View Subject | View Object

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p(HGNC:MAPT, var("p.Val277Met")) increases path(HBP:neurotoxicity) View Subject | View Object

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p(HGNC:MAPT, var("p.Val277Met")) decreases bp(GO:"nervous system development") View Subject | View Object

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Evidence 0a28e0e357
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In add- ition, only FL Tau V337M was phosphorylated at the KXGS motif (Fig. 2A, mid panel, 12E8), S396 and S404 (PHF-1 epitope) (Fig. 2A, lower panel, PHF-1).

p(HGNC:MAPT, var("p.Val277Met")) increases p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

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p(HGNC:MAPT, var("p.Val277Met")) increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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