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Rat PC12 wild-type cells with polypharmacological drug PHOX15 treatment that reduces tau phosphorylation at disease-relevant sites and restores its physiological microtubule interaction

ABSTRACT: In tauopathies such as Alzheimer's disease, the aggregation and increased phosphorylation of tau proteins are key pathological features. These changes in tau are strongly linked to neurodegeneration, making it a prime target for therapeutic intervention. Through chemoinformatic analyses, 2-phenyloxazole (PHOX) derivatives were identified as promising polypharmacological agents that could inhibit tau aggregation and modulate its phosphorylation. PHOX15 has been shown to restore the normal interaction of tau with microtubules in neurons and inhibit the initial phase of tau aggregation in vitro. Additionally, PHOX15 has been observed to suppress the activity of significant tau kinases, namely GSK3β and Cdk5, and decrease tau phosphorylation at sites relevant to disease progression. Molecular dynamics simulations have revealed that PHOX15's binding in tau protofilaments may hinder their transformation into PHF-like conformations. Complementary mass spectrometry experiments in Rat PC12 wild-type cells treated with PHOX15 demonstrated notable alterations in the kinome upon this treatment. This project highlights the potential of PHOX15 as a valuable drug candidate to mitigate tau-induced neurodegeneration. For more details, see Pinzi L, Conze C et al. “Quantitative Live Cell Imaging of a Tauopathy Model Enables the Identification of a Polypharmacological Drug Candidate That Restores Physiological Microtubule Regulation.” BioRxiv, 2022. https://doi.org/10.1101/2022.10.31.514565.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Nataliya Trushina

LAB HEAD: Roland Brandt

PROVIDER: PXD048913 | Pride | 2024-02-26

REPOSITORIES: Pride

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			Action	DRS
	CC_DMSO_enriched_1.raw	Raw
	CC_DMSO_enriched_1.raw.refined.mgf	Mgf
	CC_DMSO_enriched_2.raw	Raw
	CC_DMSO_enriched_2.raw.mzxml	Mzxml
	CC_DMSO_enriched_2.raw.refined.mgf	Mgf

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Project description:In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) and Gerstmann-Sträussler-Scheinker (GSS) disease, two genetically determined Prion protein (PrP) amyloidoses characterized by the deposition of PrP amyloid (APrP) in the vessel walls and in the cerebral parenchyma, respectively. A nonsense and a missense mutation in the PRNP gene lead to a premature termination of translation at codon position 160 (Q160Ter) of PrP in PrP-CAA, or to the substitution of an amino acid at residue 198 (F198S) of PrP in GSS. These two diseases have different clinical and pathologic phenotypes; however, in both diseases, neuropathologic analyses have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA and GSS are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA, Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA and GSS brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA and GSS are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

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Rat PC12 wild-type cells with polypharmacological drug PHOX15 treatment that reduces tau phosphorylation at disease-relevant sites and restores its physiological microtubule interaction

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