The mechanism of Hsp90-induced oligomerizaton of Tau

Weickert, Sabrina; Wawrzyniuk, Magdalena; John, Laura; Rüdiger, Stefan; Drescher, Malte

doi:10.1126/sciadv.aax6999

Cited by 59 publications

(47 citation statements)

References 65 publications

(99 reference statements)

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“…Moreover, HSPs and protein disaggregases are also implicated in combating protein misfolding and aberrant protein aggregation [ 57 , 58 ]. HSPs (e.g., Hsp70 and Hsp90) are important inhibitors of protein aggregation by protecting the exposed hydrophobic regions from aggregation [ 59 , 60 , 61 ]. Yeast Hsp104 can reverse toxic aggregates formed by α-synuclein, tau, Aβ, PrP and amylin [ 62 , 63 ], thus reducing the toxic species and restoring native function to proteins sequestered within aggregates [ 59 ].…”

Section: Regulation Of Functional Amyloid-like Aggregate Formationmentioning

confidence: 99%

Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins

Sheng

Olrichs

Gadella

et al. 2020

IJMS

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The idea that amyloid fibrils and other types of protein aggregates are toxic for cells has been challenged by the discovery of a variety of functional aggregates. However, an identification of crucial differences between pathological and functional aggregation remains to be explored. Functional protein aggregation is often reversible by nature in order to respond properly to changing physiological conditions of the cell. In addition, increasing evidence indicates that fast fibril growth is a feature of functional amyloids, providing protection against the long-term existence of potentially toxic oligomeric intermediates. It is becoming clear that functional protein aggregation is a complexly organized process that can be mediated by a multitude of biomolecular factors. In this overview, we discuss the roles of diverse biomolecules, such as lipids/membranes, glycosaminoglycans, nucleic acids and metal ions, in regulating functional protein aggregation. Our studies on the protein GAPR-1 revealed that several of these factors influence the amyloidogenic properties of this protein. These observations suggest that GAPR-1, as well as the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related proteins group 1 (CAP) superfamily of proteins that it belongs to, require the assembly into an amyloid state to exert several of their functions. A better understanding of functional aggregate formation may also help in the prevention and treatment of amyloid-related diseases.

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Section: Regulation Of Functional Amyloid-like Aggregate Formationmentioning

confidence: 99%

Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins

Sheng

Olrichs

Gadella

et al. 2020

IJMS

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“…Although Hsp90 is normally thought to act as cellular protection during stress, Hsp90 binding to tau at the VQIVYK motif facilitates a conformational change that results in its phosphorylation by glycogen synthase kinase 3, which further promotes tau aggregation [ 28 ]. Additionally, a recent study found that Hsp90 binding to tau uncovered the repeat domains by conformationally opening the ‘paper-clip’ structure of tau, suggesting that the formation of tau oligomers was caused by the conversion of tau monomers from inert to aggregation-prone forms [ 29 ].…”

Section: Factors Involved In the Formation Of Tau Seedsmentioning

confidence: 99%

Critical Molecular and Cellular Contributors to Tau Pathology

2021

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Tauopathies represent a group of neurodegenerative diseases including Alzheimer’s disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic ‘tau seeds’ from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells—including phagocytotic microglial and astroglial phenotypes—have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies—an increase in the presence of the ε2 allele of apolipoprotein E (ApoE)—provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies.

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“…In line with this, HSPB1 overexpression decreased Tau levels and rescued the Tau mediated damage in a mouse model (Abisambra et al, 2010 ). Interestingly, HSP90 stabilizes aggregation-prone conformations of Tau and promotes oligomer formation in vitro (Weickert et al, 2020 ). However, the fate of Tau is highly dependent on the specific HSP90 co-chaperone (Shelton et al, 2017 ).…”

Section: The Role Of Chaperones In Prion-like Propagationmentioning

confidence: 99%

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Tittelmeier

Nachman

Nussbaum-Krammer

2020

Front. Aging Neurosci.

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Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.

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The mechanism of Hsp90-induced oligomerizaton of Tau

Cited by 59 publications

References 65 publications

Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins

Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins

Critical Molecular and Cellular Contributors to Tau Pathology

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

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