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Article ; Online: Tau Lysine Pseudomethylation Regulates Microtubule Binding and Enhances Prion-like Tau Aggregation.

Xia, Yuxing / Bell, Brach M / Giasson, Benoit I

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: Alzheimer's disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by ... ...

Abstract	Alzheimer's disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by various post-translational modifications (PTMs) that include phosphorylation, acetylation, and methylation. Tau methylation has emerged as a target of interest for its potential involvement in tau pathomechanisms. Filamentous tau aggregates isolated from patients with AD are methylated at multiple lysine residues, although the exact methyltransferases have not been identified. One strategy to study the site-specific effects of methylation is to create methylation mimetics using a KFC model, which replaces lysine (K) with a hydrophobic group such as phenylalanine (F) to approximate the effects of lysine methylation (C or methyl group). In this study, tau methylmimetics were used to model several functional aspects of tau methylation such as effects on microtubule binding and tau aggregation in cell models. Overall, several tau methylmimetics displayed impaired microtubule binding, and tau methylmimetics enhanced prion-like seeded aggregation in the context of the FTD tau mutation P301L. Like other PTMs, tau methylation is a contributing factor to tau pathogenesis and could be a potential therapeutic drug target for the treatment of different tauopathies.
MeSH term(s)	Humans ; tau Proteins/metabolism ; Lysine/metabolism ; Prions/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Alzheimer Disease/metabolism ; Tauopathies/metabolism ; Pick Disease of the Brain/metabolism ; Microtubules/metabolism
Chemical Substances	tau Proteins ; Lysine (K3Z4F929H6) ; Prions
Language	English
Publishing date	2023-05-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24098286
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Article ; Online: Tau Lysine Pseudomethylation Regulates Microtubule Binding and Enhances Prion-like Tau Aggregation

Yuxing Xia / Brach M. Bell / Benoit I. Giasson

International Journal of Molecular Sciences, Vol 24, Iss 8286, p

2023 Volume 8286

Abstract: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by ... ...

Abstract	Alzheimer’s disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by various post-translational modifications (PTMs) that include phosphorylation, acetylation, and methylation. Tau methylation has emerged as a target of interest for its potential involvement in tau pathomechanisms. Filamentous tau aggregates isolated from patients with AD are methylated at multiple lysine residues, although the exact methyltransferases have not been identified. One strategy to study the site-specific effects of methylation is to create methylation mimetics using a KFC model, which replaces lysine (K) with a hydrophobic group such as phenylalanine (F) to approximate the effects of lysine methylation (C or methyl group). In this study, tau methylmimetics were used to model several functional aspects of tau methylation such as effects on microtubule binding and tau aggregation in cell models. Overall, several tau methylmimetics displayed impaired microtubule binding, and tau methylmimetics enhanced prion-like seeded aggregation in the context of the FTD tau mutation P301L. Like other PTMs, tau methylation is a contributing factor to tau pathogenesis and could be a potential therapeutic drug target for the treatment of different tauopathies.
Keywords	Alzheimer’s disease ; frontotemporal dementia ; tau protein ; tauopathies ; methylation ; aggregation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: Tau mutation S356T in the three repeat isoform leads to microtubule dysfunction and promotes prion-like seeded aggregation.

Xia, Yuxing / Bell, Brach M / Kim, Justin D / Giasson, Benoit I

Frontiers in neuroscience

2023 Volume 17, Page(s) 1181804

Abstract: Tauopathies are a group of neurodegenerative diseases, which include frontotemporal dementia (FTD) and Alzheimer's disease (AD), broadly defined by the development of tau brain aggregates. Both missense and splicing tau mutations can directly cause early ...

Abstract	Tauopathies are a group of neurodegenerative diseases, which include frontotemporal dementia (FTD) and Alzheimer's disease (AD), broadly defined by the development of tau brain aggregates. Both missense and splicing tau mutations can directly cause early onset FTD. Tau protein is a microtubule-associated protein that stabilizes and regulates microtubules, but this function can be disrupted in disease states. One contributing factor is the balance of different tau isoforms, which can be categorized into either three repeat (3R) or four repeat (4R) isoforms based on the number of microtubule-binding repeats that are expressed. Imbalance of 3R and 4R isoforms in either direction can cause FTD and neurodegeneration. There is also increasing evidence that 3R tauopathies such as Pick's disease form tau aggregates predominantly comprised of 3R isoforms and these can present differently from 4R and mixed 3R/4R tauopathies. In this study, multiple mutations in 3R tau were assessed for MT binding properties and prion-like aggregation propensity. Different missense tau mutations showed varying effects on MT binding depending on molecular location and properties. Of the mutations that were surveyed, S356T tau is uniquely capable of prion-like seeded aggregation and forms extensive Thioflavin positive aggregates. This unique prion-like tau strain will be useful to model 3R tau aggregation and will contribute to the understanding of diverse presentations of different tauopathies.
Language	English
Publishing date	2023-05-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1181804
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Article ; Online: Correction: Collusion of α-Synuclein and Aβ aggravating co-morbidities in a novel prion-type mouse model.

Lloyd, Grace M / Dhillon, Jess-Karan S / Gorion, Kimberly-Marie M / Riffe, Cara / Fromholt, Susan E / Xia, Yuxing / Giasson, Benoit I / Borchelt, David R

Molecular neurodegeneration

2024 Volume 19, Issue 1, Page(s) 17

Language	English
Publishing date	2024-02-16
Publishing country	England
Document type	Published Erratum
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-024-00710-2
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Article ; Online: The emerging role of α-synuclein truncation in aggregation and disease.

Sorrentino, Zachary A / Giasson, Benoit I

The Journal of biological chemistry

2020 Volume 295, Issue 30, Page(s) 10224–10244

Abstract: α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system ... ...

Abstract	α-Synuclein (αsyn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further αsyn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why αsyn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of αsyn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of αsyn may modulate the propensity of αsyn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms of αsyn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to αsyn upon truncation; and 5) discuss pathways through which truncated αsyn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of αsyn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of αsyn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of αsyn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.
MeSH term(s)	Animals ; Humans ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurodegenerative Diseases/therapy ; Protein Aggregation, Pathological/genetics ; Protein Aggregation, Pathological/metabolism ; Protein Aggregation, Pathological/pathology ; Protein Aggregation, Pathological/therapy ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
Chemical Substances	SNCA protein, human ; alpha-Synuclein
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.REV120.011743
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Article ; Online: Exploring the Peripheral Initiation of Parkinson's Disease in Animal Models.

Sorrentino, Zachary A / Giasson, Benoit I

Neuron

2019 Volume 103, Issue 4, Page(s) 547–549

Abstract: Parkinson's disease is a neurodegenerative movement disorder; however, peripheral symptoms can arise decades prior. In this issue of Neuron, Kim et al. (2019) provide evidence that progressive α-synuclein aggregation initiating in the gut could be a ... ...

Abstract	Parkinson's disease is a neurodegenerative movement disorder; however, peripheral symptoms can arise decades prior. In this issue of Neuron, Kim et al. (2019) provide evidence that progressive α-synuclein aggregation initiating in the gut could be a pathogenic epicenter anatomically rippling throughout the nervous system.
MeSH term(s)	Animals ; Brain ; Disease Models, Animal ; Neurodegenerative Diseases ; Parkinson Disease ; alpha-Synuclein
Chemical Substances	alpha-Synuclein
Language	English
Publishing date	2019-08-22
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2019.07.031
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Article ; Online: Human tauopathy strains defined by phosphorylation in R1-R2 repeat domains of tau.

Smith, Ethan D / Vo, Quan / Giasson, Benoit I / Borchelt, David R / Prokop, Stefan / Chakrabarty, Paramita

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 172

Abstract: Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights ...

Abstract	Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr → Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies.
MeSH term(s)	Humans ; tau Proteins/metabolism ; Phosphorylation ; Detergents ; Tauopathies/genetics ; Tauopathies/metabolism ; Alzheimer Disease/metabolism
Chemical Substances	tau Proteins ; Detergents
Language	English
Publishing date	2023-10-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01664-0
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Article ; Online: "Don't Phos Over Tau": recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer's disease and other tauopathies.

Xia, Yuxing / Prokop, Stefan / Giasson, Benoit I

Molecular neurodegeneration

2021 Volume 16, Issue 1, Page(s) 37

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Alzheimer Disease/metabolism ; Biomarkers/metabolism ; Humans ; Phosphorylation ; Protein Processing, Post-Translational ; tau Proteins/metabolism
Chemical Substances	Biomarkers ; MAPT protein, human ; tau Proteins
Language	English
Publishing date	2021-06-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/s13024-021-00460-5
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Article ; Online: Tau K321/K353 pseudoacetylation within KXGS motifs regulates tau-microtubule interactions and inhibits aggregation.

Xia, Yuxing / Bell, Brach M / Giasson, Benoit I

Scientific reports

2021 Volume 11, Issue 1, Page(s) 17069

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Acetylation ; Amino Acid Motifs ; HEK293 Cells ; Humans ; Microtubules/metabolism ; Mutation ; Protein Binding ; Protein Multimerization ; Protein Processing, Post-Translational ; tau Proteins/chemistry ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2021-08-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-96627-7
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Article ; Online: Pathogenic MAPT mutations Q336H and Q336R have isoform-dependent differences in aggregation propensity and microtubule dysfunction.

Xia, Yuxing / Nasif, Lith / Giasson, Benoit I

Journal of neurochemistry

2021 Volume 158, Issue 2, Page(s) 455–466

Abstract: Tauopathies are a group of heterogeneous neurodegenerative disorders characterized by brain deposition of tau inclusions. These insidious disorders include Alzheimer's disease and frontotemporal dementia, the two leading causes of dementia. Mutations in ... ...

Abstract	Tauopathies are a group of heterogeneous neurodegenerative disorders characterized by brain deposition of tau inclusions. These insidious disorders include Alzheimer's disease and frontotemporal dementia, the two leading causes of dementia. Mutations in the microtubule-associated protein tau (MAPT) gene lead to familial forms of frontotemporal dementia. Previously, we used cell-based assays to screen over 20 missense tau mutations and found that decreased microtubule (MT) binding affinity was the most shared property. As a break from this trend, the MAPT mutations Q336H and Q336R are thought to promote MT assembly rather than inhibit it based on in vitro studies. Q336H and Q336R MAPT mutations also cause early onset frontotemporal dementia with Pick bodies, which are mostly composed of 3R tau isoforms. To provide further insights on the pathobiology of these mutations, we assessed Q336H and Q336R tau mutants for aggregation propensity and MT binding in cell-based assays in the context of both 0N3R and 0N4R tau isoforms. Q336R tau was prone to prion-like seeded aggregation but both Q336H and Q336R tau led to increased MT binding. Additionally, we found that different tau isoforms with these mutations heterogeneously regulate different MT subpopulations of tyrosinated and acetylated MTs, markers of newly formed MTs and stable MTs. The Q336H and Q336R tau mutations may exemplify an alternative mechanism where pathogenic tau can bind MTs with higher affinity and hyperstabilize MTs, which prevent proper MT regulation and homeostasis.
MeSH term(s)	Frontotemporal Dementia/genetics ; HEK293 Cells ; Humans ; Isomerism ; Microtubules/genetics ; Mutagenesis, Site-Directed ; Mutation/genetics ; Pick Disease of the Brain/genetics ; Protein Processing, Post-Translational ; Tauopathies/genetics ; tau Proteins/chemistry ; tau Proteins/genetics
Chemical Substances	MAPT protein, human ; tau Proteins
Language	English
Publishing date	2021-04-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.15358
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