Phosphorylation of serine 305 in tau inhibits aggregation

Strang, Kevin H.; Sorrentino, Zachary A.; Riffe, Cara J.; Gorion, Kimberly-Marie M.; Vijayaraghavan, Niran; Golde, Todd E.; Giasson, Benoit I.

doi:10.1016/j.neulet.2018.11.011

Cited by 29 publications

(31 citation statements)

References 42 publications

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“…The sequence recognized by AT100 and pS396 antibodies is conserved in human and in Syrian hamster-a small mammal with the capacity to hibernate under adverse conditions [51], which suggests that these phosphorylations could also be reversed in AD cases. In others studies, it has been described that phosphorylation of tau on threonine 205 may have a protective role by preventing A␤-induced excitotoxicity [52] and that serine 305 phosphorylation inhibits tau aggregation [53]. In addition, in vitro experiments revealed that phosphorylation of threonine 212 may inhibit the toxic aggregation of tau [23].…”

Section: Discussionmentioning

confidence: 96%

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Regalado-Reyes

Furcila

Hernández

et al. 2019

JAD

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Despite extensive studies regarding tau phosphorylation progression in both human Alzheimer's disease cases and animal models, the molecular and structural changes responsible for neurofibrillary tangle development are still not well understood. Here, by using the antibodies AT100 (recognizes tau protein phosphorylated at Thr212 and Ser214 in the proline-rich region) and pS396 (recognizes tau protein phosphorylated at serine residue 396 in the C-terminal region), we examined phospho-tau immunostaining in neurons from the hippocampal CA1 region of 21 human cases with tau pathology ranging from Braak stage I to VI. Our results indicate that the AT100/pS396 ratio decreases in CA1 in accordance with the severity of the disease, along with its colocalization. We therefore propose the AT100/pS396 ratio as a new tool to analyze the tau pathology progression. Our findings also suggest a conformational modification in tau protein that may cause the disappearance of the AT100 epitope in the late stages of tau pathology, which may play a role in the toxic tangle aggregation. Thus, this study provides new insights underlying the stages for the formation of neurofibrillary tangles in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 96%

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Regalado-Reyes

Furcila

Hernández

et al. 2019

JAD

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“…This may help to explain why Tau is prone to self-assemble and co-aggregate in some cases of Lewy body-associated diseases. In addition to S129, several other phosphorylation sites were identified within or adjacent to the binding interface of α-syn and K19, including Y125 and Y136 in α-syn as well as S320 in K19 (54,55). Further research is warranted to clarify how such modifications, as well as disease familial disease-associated mutations (e.g.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation

Zhang

et al. 2020

Journal of Biological Chemistry

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Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric α-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading to their co-aggregation in vitro. NMR spectroscopy experiments revealed that α-syn uses its highly negatively charged C terminus to directly interact with Tau23 and K19. Deletion of the C terminus effectively abolished its binding to Tau23 and K19 as well as its synergistic effect on promoting their fibrillation. Moreover, an S129D substitution of α-syn, mimicking C-terminal phosphorylation of Ser129 in α-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated α-syn phosphorylation levels, significantly enhanced the activity of α-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between α-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of α-syn and Tau in neurodegenerative diseases.

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“…Triple phosphorylation at Ser202/Thr205/Ser208 has been proposed to be a combination that leads to rapid tau aggregation [ 51 , 77 ]. On the other hand, phosphorylation sites such as Ser214, Ser262, and Ser305 have been demonstrated to inhibit tau aggregation and may be neuroprotective [ 78 , 79 ]. In late disease stages, the hyperphosphorylation of multiple pro-aggregation sites may overcome protective ones.…”

Section: Main Textmentioning

confidence: 99%

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Xia

Prokop

Giasson

2021

Mol Neurodegeneration

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118

110

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Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

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Phosphorylation of serine 305 in tau inhibits aggregation

Cited by 29 publications

References 42 publications

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Phospho-Tau Changes in the Human CA1 During Alzheimer’s Disease Progression

Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

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