14–3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity DOI Creative Commons
Bing Wang, Mary Gannon, Rudradip Pattanayak

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106801 - 106801

Published: Jan. 1, 2025

Aggregation of alpha-synuclein (αsyn) plays an integral role in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). 14-3-3θ is a highly expressed brain protein chaperone-like activity that regulates αsyn folding. overexpression reduces aggregation, transmission between cells, neuronal loss, while 14-3-3 inhibition promotes pathology. We previously observed increased phosphorylation at serine 232 human PD DLB brains. Here we examine phosphorylation's effects on aggregation toxicity. Using paracrine model, found the non-phosphorylatable S232A protected phosphomimetic S232D failed to protect against The mutant reduced oligomerization released did not. showed significant reduction binding compared wildtype or 14-3-3θ. knock-in mouse models expressing mutation cortex hippocampus, examined impact S232 preformed fibril (PFF) model. Primary neurons from mice inclusion formation Cre control upon PFF treatment. In contrast, inclusions. αSyn injection into dorsolateral striatum induced higher numbers sensorimotor mice. conclusion, interrupts ability bind regulate aggregation. Increased likely accelerates neurodegeneration these disorders.

Language: Английский

Sex differences for regional pathology in people with a high likelihood of Lewy body dementia phenotype based on underlying pathology DOI Creative Commons
Ece Bayram, David G. Coughlin, Shunsuke Koga

et al.

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 1, 2025

Clinicopathological correlations differ by sex in Lewy body dementia (LBD). However, previous studies have focused on pathological staging systems that place less emphasis regional pathologies. We included 357 people (131 female, 226 male) with a high likelihood of LBD based pathology from the Brain Bank for Neurodegenerative (Jacksonville, FL). Sex differences body, senile plaque, and neurofibrillary tangle counts their associations clinical diagnosis were assessed. Females likely to diagnosis; they had more bodies, tangles, plaques various regions than males (all p's < 0.05). A higher was associated middle frontal, cingulate, entorhinal pathology, so females 0.045). clinicopathological also occur at level. frequency misdiagnosis males. risk underdiagnosis (LBD) males.Regional LBD.Regional association differs sex.Regional stronger phenotype

Language: Английский

Citations

1
Widespread distribution of α-synuclein oligomers in LRRK2-related Parkinson’s disease DOI
Hiroaki Sekiya, L. Franke, Yuki Hashimoto

et al.

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: May 2, 2025

Language: Английский

Citations

1
14–3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity DOI Creative Commons
Bing Wang, Mary Gannon, Rudradip Pattanayak

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106801 - 106801

Published: Jan. 1, 2025

Aggregation of alpha-synuclein (αsyn) plays an integral role in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). 14-3-3θ is a highly expressed brain protein chaperone-like activity that regulates αsyn folding. overexpression reduces aggregation, transmission between cells, neuronal loss, while 14-3-3 inhibition promotes pathology. We previously observed increased phosphorylation at serine 232 human PD DLB brains. Here we examine phosphorylation's effects on aggregation toxicity. Using paracrine model, found the non-phosphorylatable S232A protected phosphomimetic S232D failed to protect against The mutant reduced oligomerization released did not. showed significant reduction binding compared wildtype or 14-3-3θ. knock-in mouse models expressing mutation cortex hippocampus, examined impact S232 preformed fibril (PFF) model. Primary neurons from mice inclusion formation Cre control upon PFF treatment. In contrast, inclusions. αSyn injection into dorsolateral striatum induced higher numbers sensorimotor mice. conclusion, interrupts ability bind regulate aggregation. Increased likely accelerates neurodegeneration these disorders.

Language: Английский

Citations

0