Pathogenic MAPT mutations Q336H and Q336R have isoform‐dependent differences in aggregation propensity and microtubule dysfunction

Xia, Yuxing; Nasif, Lith H.

doi:10.1111/jnc.15358

Cited by 8 publications

(23 citation statements)

References 64 publications

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“…However, this effect did not appear to be additive, which suggests single acetylation sites at either K321 or K353 could be sufficient to prevent or slow the formation of tau filaments. Paradoxically, increased pseudoacetylation of these same sites also decreased MT binding, which is thought to be a detrimental effect associated with many tau missense mutations 19 , 39 . Pseudoacetylation is a model of constitutive acetylation and physiologic baseline levels of tau acetylation may be low enough that normally MTs are minimally affected.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…K18 amyloid tau seeds were generated from the tau protein fragment K18, which contains the MT binding repeats from Q244 to E372 (numbering based on 2N4R full length tau) as previously described 19 , 26 , 39 .…”

Section: Methodsmentioning

confidence: 99%

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

Xia

Bell

2021

Sci Rep

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“…Alternative splicing is common in neuronal cells which help to increase genetic plasticity and the diversity of proteome under physiological conditions [6]. However, imbalance in the ratio of the 3R and 4R isoforms can give rise to the pathogenesis of tauopathies, as the 4R tau is more efficient in promoting microtubule assembly with an extra repeat domain R2 which hyper-stabilize MT and more free-floating tau leads to aggregates formation [3,6,7] identified 7 patients via postmortem examination, only 2 were female. Most patients died at 64 years old with median survival time being 3 months (0.5-36) [28].…”

Section: Epidemiology Of Tauopathiesmentioning

confidence: 99%

“…A growing body of literature elucidates the downstream events of tau mutations, including enhanced tau aggregation, dysfunction in mRNA splicing and tau structure alteration [7].…”

Section: Mapt Mutationsmentioning

confidence: 99%

Tauopathies: new perspectives and challenges

Zhang

Liu

et al. 2022

Mol Neurodegeneration

131

114

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Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics. Conclusions Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.

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“…Another MAPT mutation at the same codon, Q336R, has the same effect on tau aggregation [4,5]. A recent study has discovered an increased tau-microtubule interaction caused by both mutations, thus describing a new and unique mechanism [6,7]. Carriers of MAPT mutations may have variable clinical phenotypes, with most patients presenting with behavioral variant FTD (bvFTD) and other clinical phenotypes, ranging from Alzheimer disease (AD)-like to corticobasal syndrome [8].…”

Section: Introductionmentioning

confidence: 99%

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

Villa

Rossi

Bizzozero

et al. 2022

Euro J of Neurology

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Background and purpose: Q336H is a rare MAPT mutation, previously found in a single patient with behavioral variant frontotemporal dementia and tau pathology (Pick bodies).Here, we describe the clinical characteristics of two members of a new family carrying the Q336H MAPT mutation.Methods: Clinical, genetic, and neuroradiological assessment and follow-up of the proband were made.Results: At age 37 years, the proband developed naming and object recognition impairment, due to a lack of knowledge. After 3 years, he developed behavioral disorders.Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography showed the involvement of the left temporal pole. A diagnosis of semantic variant primary progressive aphasia (svPPA) was made. At follow-up after 6 and 12 months, a rapid worsening of cognitive deficits occurred. His parent presented, at age 65 years, slowly progressive memory deficits without behavioral impairment, and, on MRI, evidence of mesial temporal atrophy, consistent with a clinical diagnosis of Alzheimer disease (AD).Conclusions: This is the second family carrying the MAPT Q336H mutation reported so far. We showed that svPPA and AD-like phenotype can be associated with this mutation. A wide clinical variability exists at the intrafamilial level for Q336H MAPT mutation, pointing to genetic and/or environmental influencing factors on disease expression. We also confirmed that svPPA can be associated with MAPT mutations, suggesting that this gene should be analyzed also in patients with svPPA, especially with early onset. In addition, an AD-like phenotype may be associated with this mutation, suggesting its different effects on protein misfolding and aggregation.

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Pathogenic MAPT mutations Q336H and Q336R have isoform‐dependent differences in aggregation propensity and microtubule dysfunction

Cited by 8 publications

References 64 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

Tauopathies: new perspectives and challenges

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

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