Tauopathies such as Alzheimer’s disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau’s pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau’s physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament’s ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction / Pinzi, L.; Conze, C.; Bisi, N.; Torre, G. D.; Soliman, A.; Monteiro-Abreu, N.; Trushina, N. I.; Krusenbaum, A.; Dolouei, M. K.; Hellwig, A.; Christodoulou, M. S.; Passarella, D.; Bakota, L.; Rastelli, G.; Brandt, R.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 15:1(2024), pp. 1-16. [10.1038/s41467-024-45851-6]

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction

Pinzi L.;Rastelli G.
;
Brandt R.
2024

Abstract

Tauopathies such as Alzheimer’s disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau’s pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau’s physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament’s ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.
2024
15
1
1
16
Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction / Pinzi, L.; Conze, C.; Bisi, N.; Torre, G. D.; Soliman, A.; Monteiro-Abreu, N.; Trushina, N. I.; Krusenbaum, A.; Dolouei, M. K.; Hellwig, A.; Christodoulou, M. S.; Passarella, D.; Bakota, L.; Rastelli, G.; Brandt, R.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 15:1(2024), pp. 1-16. [10.1038/s41467-024-45851-6]
Pinzi, L.; Conze, C.; Bisi, N.; Torre, G. D.; Soliman, A.; Monteiro-Abreu, N.; Trushina, N. I.; Krusenbaum, A.; Dolouei, M. K.; Hellwig, A.; Christodoulou, M. S.; Passarella, D.; Bakota, L.; Rastelli, G.; Brandt, R.
File in questo prodotto:
File Dimensione Formato  
Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction_NatCommun2024.pdf

Open access

Tipologia: Versione pubblicata dall'editore
Dimensione 3.87 MB
Formato Adobe PDF
3.87 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1340311
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact