Cellular Uptake of Tau Aggregates Triggers Disulfide Bond Formation in Four-Repeat Tau Monomers DOI Creative Commons

Brad J. Krzesinski,

Tyler J. Holub,

Zachariah Y. Gabani

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Oxidative stress is an important driver of aging and has been linked to numerous neurodegenerative disorders, including Alzheimer's disease. A key pathological hallmark are filamentous inclusions made the microtubule associated protein Tau. Based on alternative splicing, Tau can feature either three or four binding repeats. Distinctively, three-repeat contains a single cysteine; four-repeat two. Although there evidence that cysteines in filaments exist reduced form, very little known about disulfide-bonded state. It unclear whether it nontransiently reducing environment cytosol. Such knowledge, however, as different redox states could modulate aggregation. To address this question, we transfected HEK293 cells expressing P301S variant with fibril seeds composed compact, monomers. In vitro, these fibrils observed recruit only compact Tau, but not which replaced by alanines serines. line characteristic, dissociate when treated agent. When offered cells, recruited forming intracellular same seeding properties vitro counterparts. Markedly, proteins have configuration upon reduction. These findings reveal uptake exogeneous triggers oxidation monomers, modulating

Language: Английский

Impact of frequent ARID1A mutations on protein stability provides insights into cancer pathogenesis DOI Creative Commons
Rajen Goutam, Gangtong Huang, Exequiel Medina

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 24, 2025

Language: Английский

Citations

0
Determinants for Substoichiometric Inhibition of IAPP and Aβ Amyloid Aggregations by Bri2 BRICHOS DOI
Zhenzhen Zhang, Gangtong Huang, Shivani Gupta

et al.

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Bri2 BRICHOS, a folded domain of the transmembrane protein expressed in both brain and pancreas, is an experimentally known substoichiometric inhibitor amyloid aggregation. The molecular chaperone effectively delays fibrillization at low molar ratios for β-amyloid (Aβ) Alzheimer's disease (AD) islet polypeptide (IAPP) type 2 diabetes (T2D). While discovering effective antiamyloid inhibitors that work doses appealing strategy to mitigate toxicity, mechanism underlying broad efficient activity BRICHOS remains unknown. Here, we computationally demonstrated exhibits stronger binding affinity fibril seeds than monomers using atomistic discrete dynamic simulations. By competing with bind active elongation sites on newly nucleated, weakly populated seeds, small amount could block rapid growth via monomer addition. observed differential inhibition efficiency against IAPP Aβ aggregation was found depend relative fibril-binding affinities compared those self-seeding monomers. Our derived determinants by may inform future design potent therapies AD, T2D, other diseases.

Language: Английский

Citations

0
Dimerization of the Aβ42 under the Influence of the Gold Nanoparticle: A REMD Study DOI
Quynh Mai Thai, Nguyễn Thanh Tùng,

Dung Do Thi

et al.

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(47), P. 11705 - 11713

Published: Nov. 7, 2024

Advances in Alzheimer's disease (AD) are related to the oligomerization of Amyloid β (Aβ) peptides. Therefore, alteration process can prevent AD. We investigated Aβ

Language: Английский

Citations

1
Cellular Uptake of Tau Aggregates Triggers Disulfide Bond Formation in Four-Repeat Tau Monomers DOI Creative Commons

Brad J. Krzesinski,

Tyler J. Holub,

Zachariah Y. Gabani

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Oxidative stress is an important driver of aging and has been linked to numerous neurodegenerative disorders, including Alzheimer's disease. A key pathological hallmark are filamentous inclusions made the microtubule associated protein Tau. Based on alternative splicing, Tau can feature either three or four binding repeats. Distinctively, three-repeat contains a single cysteine; four-repeat two. Although there evidence that cysteines in filaments exist reduced form, very little known about disulfide-bonded state. It unclear whether it nontransiently reducing environment cytosol. Such knowledge, however, as different redox states could modulate aggregation. To address this question, we transfected HEK293 cells expressing P301S variant with fibril seeds composed compact, monomers. In vitro, these fibrils observed recruit only compact Tau, but not which replaced by alanines serines. line characteristic, dissociate when treated agent. When offered cells, recruited forming intracellular same seeding properties vitro counterparts. Markedly, proteins have configuration upon reduction. These findings reveal uptake exogeneous triggers oxidation monomers, modulating

Language: Английский

Citations

0