A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation

Ajit, Deepa; Trzeciakiewicz, Hanna; Tseng, Jui-Heng; Wander, Connor M.; Chen, Youjun; Ajit, Aditi; King, Diamond P.; Cohen, Todd J.

doi:10.1074/jbc.ra119.009674

Cited by 14 publications

(14 citation statements)

References 52 publications

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“…The actual protein structure and sequence required for Thioflavin S binding is still not well defined although Thioflavin S is routinely used as a marker of protein amyloid formation. However, a similar effect was also found in K280 acetylmimetic in P301S transgenic mice where K280Q significantly decreased tau filament formation and Thioflavin S reactivity 37 . Tau acetylation within the MT-binding region likely interferes with packing of beta-pleated sheets involved in amyloid formation and thus either tertiary or/and quaternary structures resulting in polymorphs, but that are still permissive to protein inclusion formation.…”

Section: Discussionsupporting

confidence: 68%

Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau–microtubule interactions and inhibits aggregation

Xia

Bell

2021

Sci Rep

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Alzheimer’s disease is the leading cause of dementia and a defining hallmark is the progressive brain deposition of tau aggregates. The insidious accumulation of brain tau inclusions is also involved in a group of neurodegenerative diseases termed frontotemporal dementias. In all of these disorders, tau aggregates are enriched in post-translational modifications including acetylation, which has recently been identified at multiple sites. While most evidence suggest that tau acetylation is detrimental and promotes tau aggregation, a few studies support that tau acetylation within the KXGS motif can be protective and inhibit tau aggregation. To model site-specific acetylation at K259, K290, K321, and K353, acetylmimetics were created by mutating lysine to glutamine residues, which approximates size and charge of acetylation. HEK293T cells were transfected to express wild type tau, tau pathogenic mutations (P301L and P301L/S320F) or tau acetylmimetics and assessed by cell-based assays for microtubule binding and tau aggregation. Acetylmimetics within the KXGS motif (K259Q, K290Q, K321Q, K353Q) leads to significant decreased tau–microtubule interactions. Acetylmimetics K321Q and K353Q within the context of the pathogenic P301L tau mutation strongly inhibited prion-like seeded aggregation. This protective effect was confirmed to decrease intrinsic aggregation of P301L/S320F tau double mutation. Surprisingly, K321Q and K353Q acetylmimetics altered the conformational structure of P301L/S320F tau to extensively impair Thioflavin S binding. Site-specific acetylation of tau at K321 and K353 could represent a natural protective mechanism against tau aggregation and could be a potential therapeutic target.

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Section: Discussionsupporting

confidence: 68%

Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau–microtubule interactions and inhibits aggregation

Xia

Bell

2021

Sci Rep

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“…Tau acetylation has been shown to disrupt its ability to stabilize microtubules and also alter its phosphorylation status, leading to tau accumulation and aggregation ( 4 , 29 , 30 ). The specific acetyl-mimetic residues found in 6K➔Q tau did not disrupt tau binding to microtubules or alter its phosphorylation (fig.…”

Section: Resultsmentioning

confidence: 99%

TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy

et al. 2021

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“…As with phosphorylation, abnormal tau acetylation also likely plays a critical role in tauopathies [ 17 – 19 ]. There are data indicating that acetylation inhibits binding of tau to microtubules, enhances tau accumulation by preventing degradation and promotes the aggregation of tau in neurons [ 20 – 22 ]. In particular, increased expression of tau acetylated at K274 and K281 appears to result in mislocalization of tau, destabilization of the cytoskeleton in the axon initial segment, and synaptic dysfunction [ 21 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model

Guha

Fischer

Johnson

et al. 2020

Mol Neurodegeneration

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Background A defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer’s disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear. Methods Human 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E, to mimic phosphorylation of a commonly observed pathological epitope, and K274/281Q, to mimic disease-associated lysine acetylation – collectively referred as “PTM-mimetics” – as well as a T231A phosphoablation mutant. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age. Genetically-encoded fluorescent biosensors were expressed in touch neurons and used to measure neuronal morphology, mitochondrial morphology, mitophagy, and macro autophagy. Results Unlike existing tau overexpression models, C. elegans single-copy expression of tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. In addition, the PTM-mimetic mutants lacked the ability to engage neuronal mitophagy in response to mitochondrial stress. Conclusions Limiting the expression of tau results in a genetic model where modifications that mimic pathologic tauopathy-associated PTMs contribute to cryptic, stress-inducible phenotypes that evolve with age. These findings and their relationship to mitochondrial stress provides a new perspective into the pathogenic mechanisms underlying AD.

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A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation

Cited by 14 publications

References 52 publications

Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau–microtubule interactions and inhibits aggregation

Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau–microtubule interactions and inhibits aggregation

TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy

Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model

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