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1.
J Biol Chem ; 298(6): 101977, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35469920

RESUMO

The posttranslational regulation of the neuronal proteome is critical for brain homeostasis but becomes dysregulated in the aged or diseased brain, in which abnormal posttranslational modifications (PTMs) are frequently observed. While the full extent of modified substrates that comprise the "PTM-ome" are slowly emerging, how the upstream enzymes catalyzing these processes are regulated themselves is not well understood, particularly in the context of neurodegeneration. Here, we describe the reciprocal regulation of a kinase, the microtubule affinity-regulating kinase 2 (MARK2), and an acetyltransferase, CREB-binding protein (CBP), two enzymes known to extensively modify tau proteins in the progression of Alzheimer's disease. We found that MARK2 negatively regulates CBP and, conversely, CBP directly acetylates and inhibits MARK2 kinase activity. These findings highlight a reciprocal negative feedback loop between a kinase and an acetyltransferase, which has implications for how PTM interplay is coordinated on substrates including tau. Our study suggests that PTM profiles occur through the posttranslational control of the master PTM remodeling enzymes themselves.


Assuntos
Proteína de Ligação a CREB/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Acetiltransferases/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Retroalimentação , Humanos , Camundongos , Microtúbulos/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas tau/genética , Proteínas tau/metabolismo
2.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803769

RESUMO

The aggregation of amyloid ß (Aß) peptides and deposition of amyloid plaques are implicated in the pathogenesis of Alzheimer's disease (AD). Therefore, blocking Aß aggregation with small molecules has been proposed as one therapeutic approach for AD. In the present study, a series of ranitidine analogs containing cyclic imide isosteres were synthesized and their inhibitory activities toward Aß aggregation were evaluated using in vitro thioflavin T assays. The structure-activity relationship revealed that the 1,8-naphthalimide moiety provided profound inhibition of Aß aggregation and structural modifications on the other parts of the parent molecule (compound 6) maintained similar efficacy. Some of these ranitidine analogs also possessed potent inhibitory activities of acetylcholinesterase (AChE), which is another therapeutic target in AD. These ranitidine analogs, by addressing both Aß aggregation and AChE, offer insight into the key chemical features of a new type of multi-target directed ligands for the pharmaceutical treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Desenho de Fármacos , Ranitidina/síntese química , Ranitidina/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Bovinos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Imidas/química , Ligantes , Agregados Proteicos/efeitos dos fármacos , Ranitidina/química
3.
J Biol Chem ; 294(45): 16698-16711, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31543505

RESUMO

Abnormal intracellular accumulation of aggregated tau is a hallmark feature of Alzheimer's disease and other tauopathies. Pathological tau can undergo a range of post-translational modifications (PTMs) that are implicated as triggers of disease pathology. Recent studies now indicate that tau acetylation, in particular, controls both microtubule binding and tau aggregation, thereby acting as a central regulator of tau's biochemical properties and providing avenues to exploit for potential therapies. Here, using cell-based assays and tau transgenic mice harboring an acetylation-mimic mutation at residue Lys-280 (K280Q), we evaluated whether this substitution modifies the neurodegenerative disease pathology associated with the aggregate-prone tau P301S variant. Strikingly, the addition of a K280Q-substituted variant altered P301S-mediated tau conformation and reduced tau hyperphosphorylation. We further evaluated neurodegeneration markers in K280Q acetylation-mimic mice and observed reduced neuroinflammation as well as restored levels of N-methyl-d-aspartate receptors and post-synaptic markers compared with the parental mice. Thus, substituting a single lysine residue in the context of a P301S disease-linked mutation produces a unique tau species that abrogates some of the cardinal features of tauopathy. The findings of our study indicate that a complex tau PTM code likely regulates tau pathogenesis, highlighting the potential utility of manipulating and detoxifying tau strains through site-specific tau-targeting approaches.


Assuntos
Tauopatias/patologia , Proteínas tau/metabolismo , Acetilação , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Estimativa de Kaplan-Meier , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , Fosforilação , Receptores de N-Metil-D-Aspartato/metabolismo , Tauopatias/metabolismo , Tauopatias/mortalidade , Proteínas tau/genética
4.
Acta Neuropathol Commun ; 12(1): 163, 2024 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-39396065

RESUMO

Tauopathies, including Alzheimer's disease (AD), are a class of neurodegenerative diseases characterized by the presence of insoluble tau inclusions. Tau phosphorylation has traditionally been viewed as the dominant post-translational modification (PTM) controlling tau function and pathogenesis in tauopathies. However, we and others have identified tau acetylation as a primary PTM regulating both normal tau function as well as abnormal pathogenic features including aggregation. Prior work showed robust tau acetylation in aggregation hotspots located within the 2nd and 3rd repeat regions of tau (residues K280 and K311) in tauopathy brains, including AD, compared to non-tauopathy controls. By screening thousands of hybridoma clones, we generated site-specific and modification-specific monoclonal antibodies targeting acetylated tau at residues K280 or K311. To validate these antibodies in a bona fide neuronal system, we targeted the acetyltransferase CBP to the cytoplasm of neurons to promote tau acetylation. Several antibody clones specifically detected CBP-acetylated tau and co-localized with ac-tau in neurons. Additionally, our lead optimal anti-acetylated-tau monoclonal antibodies detected robust tau pathology in tangles and neuritic plaques of human AD brains. Given the now emerging interest in acetylated tau as critical regulator of tau functions, these sensitive and highly specific tools will allow us to further unravel the tau PTM code and, importantly, could be deployed as diagnostic or disease-modifying agents.


Assuntos
Doença de Alzheimer , Anticorpos Monoclonais , Proteínas tau , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/imunologia , Proteínas tau/metabolismo , Proteínas tau/imunologia , Humanos , Acetilação , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Camundongos , Feminino , Processamento de Proteína Pós-Traducional , Neurônios/metabolismo , Neurônios/patologia , Idoso de 80 Anos ou mais , Idoso , Masculino
5.
Cell Rep ; 35(4): 109037, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33910013

RESUMO

The prion-like spread of tau pathology could underlie a spectrum of clinical syndromes including Alzheimer's disease (AD). Although evidence indicates that tau is transmissible, it is unclear how pathogenic tau seeds are processed in neurons. Here, we analyze fibrillar wild-type and disease-associated P301L tau seeds by using in vitro and neuronal assays. We show that P301L seeds are uniquely modified by post-translational modifications (PTMs) within the microtubule-binding region (MTBR). Although these modifications do not alter tau seed trafficking or localization, acetylated tau variants show accelerated tau aggregation, enhanced tau PTM priming, and prion-like templating. To explain the enhanced tau seed acetylation, we demonstrate that P301L seeds undergo auto-acetylation. Moreover, tau acts generally to inhibit HDAC6 deacetylase activity by preventing HDAC6 phosphorylation, leading to increased substrate acetylation. Our study highlights complex post-translational regulation of transmissible tau seeds and provides insight into the biological properties of tau strains in AD and other tauopathies.


Assuntos
Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Animais , Humanos , Camundongos
6.
Nat Commun ; 11(1): 5522, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139698

RESUMO

Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.


Assuntos
Disfunção Cognitiva/patologia , Desacetilase 6 de Histona/metabolismo , Tauopatias/patologia , Proteínas tau/metabolismo , Acetilação , Idoso , Idoso de 80 Anos ou mais , Animais , Encéfalo/patologia , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Desacetilase 6 de Histona/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosforilação , Processamento de Proteína Pós-Traducional , Tauopatias/genética , Proteínas tau/genética
7.
iScience ; 23(7): 101255, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32585593

RESUMO

The microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.

8.
Cytoskeleton (Hoboken) ; 81(1): 89-94, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38063261
9.
Sci Rep ; 7: 44102, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28287136

RESUMO

Tau acetylation has recently emerged as a dominant post-translational modification (PTM) in Alzheimer's disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule (MT)-binding region (MTBR), suggesting acetylation could regulate both normal and pathological tau functions. Here, we combined biochemical and cell-based approaches to uncover a dual pathogenic mechanism mediated by tau acetylation. We show that acetylation specifically at residues K280/K281 impairs tau-mediated MT stabilization, and enhances the formation of fibrillar tau aggregates, highlighting both loss and gain of tau function. Full-length acetylation-mimic tau showed increased propensity to undergo seed-dependent aggregation, revealing a potential role for tau acetylation in the propagation of tau pathology. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds. Our study identifies a potential "two-hit" mechanism in which tau acetylation disengages tau from MTs and also promotes tau aggregation. Thus, therapeutic approaches to limit tau K280/K281 acetylation could simultaneously restore MT stability and ameliorate tau pathology in AD and related tauopathies.


Assuntos
Processamento de Proteína Pós-Traducional , Tauopatias/metabolismo , Proteínas tau/metabolismo , Acetilação , Animais , Linhagem Celular , Humanos , Camundongos , Microtúbulos/metabolismo , Fosforilação , Agregação Patológica de Proteínas/metabolismo , Tauopatias/patologia
10.
Cell Rep ; 20(9): 2169-2183, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28854366

RESUMO

The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.


Assuntos
Desacetilase 6 de Histona/metabolismo , Neuritos/enzimologia , Neuritos/patologia , Proteínas tau/metabolismo , Acetilação , Envelhecimento/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Desacetilase 6 de Histona/antagonistas & inibidores , Humanos , Inflamação/patologia , Espectrometria de Massas , Camundongos Knockout , Fosforilação , Multimerização Proteica , Estresse Fisiológico
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