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PubMed: 30145931

Title
Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems.
Journal
Autophagy
Volume
14
Issue
None
Pages
2139-2154
Date
2018-01-01
Authors
Balaji V | Kaniyappan S | Mandelkow E | Mandelkow EM | Wang Y

Evidence 297391b7f3
JSON

Conversely, treatment with protein translation inhibitors, cycloheximide or anisomycin, alone (Fig. S8A and B) almost completely abrogated MAPT missorting (schematic in Fig. 2E). These results suggest that the dendritic MAPT is locally generated.

a(CHEBI:"(-)-anisomycin") decreases bp(GO:translation) View Subject | View Object

Appears in Networks:

a(CHEBI:"(-)-anisomycin") decreases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Appears in Networks:

a(CHEBI:cycloheximide) decreases bp(GO:translation) View Subject | View Object

Appears in Networks:

a(CHEBI:cycloheximide) decreases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Appears in Networks:

Evidence 6b69e95099
JSON

Our previous study [23] had shown that trehalose induces autophagy in primary neurons and in an N2a cell model of tauopathy, and efficiently reduces the level of MAPT and MAPT aggregation.

a(CHEBI:"alpha,alpha-trehalose") increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:"alpha,alpha-trehalose") decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 0cf37bebf0
JSON

Trehalose treatment indeed supressed the missorting of MAPT down to ~4±0.7% of dendrites, far less than the control level (~16% of dendrites) (Fig. 5B).

a(CHEBI:"alpha,alpha-trehalose") decreases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Appears in Networks:

Evidence a3db22646a
JSON

In order to determine the impact of protein degradation systems on the sorting of MAPT, we sought to suppress their activity by treating neurons on the neuritic side of the MFCs with either autophagy inhibitors, wortmannin [25] and bafilomycin A 1 [26], or with proteasomal inhibitors, epoxomicin and lactacystin [27,28].

a(CHEBI:"bafilomycin A1") decreases bp(GO:autophagy) View Subject | View Object

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a(CHEBI:epoxomicin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

Appears in Networks:

a(CHEBI:lactacystin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

Appears in Networks:

a(CHEBI:wortmannin) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence 77a559da24
JSON

Similarly, a dramatic elevation of ubiquitinated substrates (from 4.2±0.1 to 37±1) upon epoxomicin treatment was detected in dendrites containing MAPT (compare Fig. S4E and Fig. S4F).

a(CHEBI:epoxomicin) increases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

composite(a(CHEBI:epoxomicin), p(HGNC:MAPT)) increases bp(GO:"protein ubiquitination") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

Evidence 6bba18571f
JSON

Missorted dendritic MAPT showed phosphorylation mainly at the 12E8 sites upon treatment with either the autophagy inhibitor wortmannin (Fig. 4B; 57.2±9.4% dendrites) or the proteasomal inhibitor epoxomicin (Fig. 4C, 62.9±7.4% dendrites) (Fig. 4A-C, quantification in Fig. 4D), but not at the AT8 and the PHF1 (p-S396/p-S404) sites (Fig. S5, Fig 4D).

a(CHEBI:epoxomicin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:epoxomicin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:epoxomicin) causesNoChange p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:epoxomicin) causesNoChange p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:wortmannin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:wortmannin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:wortmannin) causesNoChange p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:wortmannin) causesNoChange p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation a(CHEBI:wortmannin) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation a(CHEBI:epoxomicin) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation a(CHEBI:wortmannin) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation a(CHEBI:epoxomicin) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(CHEBI:epoxomicin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

a(CHEBI:epoxomicin) causesNoChange p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

a(CHEBI:wortmannin) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

a(CHEBI:wortmannin) causesNoChange p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356)) positiveCorrelation a(CHEBI:wortmannin) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356)) positiveCorrelation a(CHEBI:epoxomicin) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

Evidence 242df0cd3b
JSON

MAPT-free dendrites in controls had a spine density of ~17 per 20-µm (17.2±0.5 per 20 µm) length, and there was a ~2- fold decrease in spine density in the MAPT-containing dendrites in neurons treated with wortmannin (7.4±1.0 per 20 µm) or epoxomicin (8.2±1.7 per 20 µm) (Fig. 6D).

a(CHEBI:epoxomicin) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:wortmannin) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

composite(a(CHEBI:epoxomicin), p(HGNC:MAPT)) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

composite(a(CHEBI:wortmannin), p(HGNC:MAPT)) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence bc3a299252
JSON

Treatment with rolipram (10 µM) on the neuritic side for 24 h (Fig. 5C) supressed missorting of MAPT down to 4.5±0.4% dendrites, far below the control level (20.5±5.6% dendrites) (Fig. 5D), thereby confirming the role of the proteasome in degrading dendritic MAPT.

a(CHEBI:rolipram) increases act(p(FPLX:Proteasome)) View Subject | View Object

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a(CHEBI:rolipram) decreases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Appears in Networks:

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, loc(MESH:Dendrites))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence fee732b31b
JSON

Compared with the MAPT-free dendrites of control neurons (Fig. S4A, 1.8±0.1), a substantial increase of SQSTM1 level (21.1±0.9) was observed in MAPT-containing dendrites upon wortmannin treatment (Fig. S4B).

a(CHEBI:wortmannin) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT) increases p(HGNC:SQSTM1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

Evidence 1f9ba67263
JSON

In addition, it has been reported that in cultured neurons, Aβ oligomers induce MAPT missorting into the somatodendritic compartment, and the missorted MAPT is phosphorylated mainly at the 12E8 (p-S262/p-S356) and AT8 (p-S202/p-T205) sites [6].

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Appears in Networks:

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 202)) positiveCorrelation a(HBP:"amyloid-beta oligomers") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation a(HBP:"amyloid-beta oligomers") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation a(HBP:"amyloid-beta oligomers") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Thr, 205)) positiveCorrelation a(HBP:"amyloid-beta oligomers") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

a(HBP:"amyloid-beta oligomers") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) positiveCorrelation a(HBP:"amyloid-beta oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356)) positiveCorrelation a(HBP:"amyloid-beta oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

Evidence d353369e4f
JSON

At more mature ages (DIV14 - DIV21), MAPT localization is mainly found in the axons with only basal levels in the somatodendritic compartment, consistent with earlier findings [20].

bp(GO:aging) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

bp(GO:aging) decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 6904a87612
JSON

Our previous work showed that inhibition of either the proteasome or autophagy in primary neurons induces pronounced neurotoxicity [23,24], making it impossible to address this issue in conventional neuron cultures.

bp(GO:autophagy) decreases path(HBP:neurotoxicity) View Subject | View Object

Appears in Networks:

act(p(FPLX:Proteasome)) decreases path(HBP:neurotoxicity) View Subject | View Object

Appears in Networks:

Evidence 3583badd16
JSON

In controls, the fraction of MAPT-containing dendrites on the neuritic side was low (~14%), but local treatment with inhibitors of either autophagy (wortmannin [Fig. 3B], bafilomycin A 1 [Fig. S3A]) or the proteasome (epoxomicin [Fig. 3C], lactacystin [Fig. S3B]) caused a pronounced 4-to 5-fold increase of MAPT-containing dendrites (to levels of ~50-76%) (Fig. 3D).

bp(GO:autophagy) decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

act(p(FPLX:Proteasome)) decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

Evidence c5c180083d
JSON

Thus, the dendritic and axonal MAPT are differentially phosphorylated. Based on this observation, we can conclude that the dendritic MAPT degraded by autophagy or proteasomal pathways is phosphorylated mainly at the 12E8 site.

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 356))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 356))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendrites

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

act(p(FPLX:Proteasome)) increases deg(p(HGNC:MAPT, pmod(Ph, Ser, 262), pmod(Ph, Ser, 356))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dendrites

Evidence 8573b0c70f
JSON

Previous studies had shown that the missorting of MAPT into dendrites can cause loss of spines [6,7].

p(HGNC:MAPT, loc(MESH:Dendrites)) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:

Evidence fb744bd496
JSON

MAPT in AD and other tauopathies is hyperphosphorylated [29] and the hyperphosphorylation has been proposed to drive the missorting of MAPT.

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

path(MESH:Tauopathies) positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

Evidence f44a2e1ee6
JSON

This observation, together with local synthesis of MAPT protein, confirms that Mapt mRNA is present in dendrites and is actively translated.

r(HGNC:MAPT, loc(MESH:Dendrites)) increases p(HGNC:MAPT, loc(MESH:Dendrites)) View Subject | View Object

Appears in Networks:

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