Activation of the Unfolded Protein Response and Proteostasis Disturbance in Parkinsonism-Dementia of Guam

Abstract Guam parkinsonism-dementia (G-PD) is a progressive and fatal neurodegenerative disorder among the native inhabitants of the Mariana Islands that manifests clinically with parkinsonism as well as dementia. Neuropathologically, G-PD is characterized by abundant neurofibrillary tangles compose...

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Vydané v:Journal of neuropathology and experimental neurology Ročník 79; číslo 1; s. 34 - 45
Hlavní autori: Verheijen, Bert M, Lussier, Celina, Müller-Hübers, Cora, Garruto, Ralph M, Oyanagi, Kiyomitsu, Braun, Ralf J, van Leeuwen, Fred W
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England Oxford University Press 01.01.2020
by American Association of Neuropathologists, Inc
Predmet:
Brain diseases
Dementia
Kinases
Proteins
Guam
United States > US
Mutant ubiquitin
TDP-43
Tauopathy
Ubiquitin-proteasome system
Autophagy
Endoplasmic reticulum stress
Guam parkinsonism-dementia
Unfolded protein response
ISSN:0022-3069, 1554-6578, 1554-6578
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Shrnutí:Abstract Guam parkinsonism-dementia (G-PD) is a progressive and fatal neurodegenerative disorder among the native inhabitants of the Mariana Islands that manifests clinically with parkinsonism as well as dementia. Neuropathologically, G-PD is characterized by abundant neurofibrillary tangles composed of hyperphosphorylated tau, marked deposition of transactive response DNA-binding protein 43 kDa (TDP-43), and neuronal loss. The mechanisms that underlie neurodegeneration in G-PD are poorly understood. Here, we report that the unfolded protein response (UPR) is activated in G-PD brains. Specifically, we show that the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein/glucose-regulated protein 78 kDa and phosphorylated (activated) ER stress sensor protein kinase RNA-like ER kinase accumulate in G-PD brains. Furthermore, proteinaceous aggregates in G-PD brains are found to contain several proteins related to the ubiquitin-proteasome system (UPS) and the autophagy pathway, two major mechanisms for intracellular protein degradation. In particular, a mutant ubiquitin (UBB+1), whose presence is a marker for UPS dysfunction, is shown to accumulate in G-PD brains. We demonstrate that UBB+1 is a potent modifier of TDP-43 aggregation and cytotoxicity in vitro. Overall, these data suggest that UPR activation and intracellular proteolytic pathways are intimately connected with the accumulation of aggregated proteins in G-PD.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0022-3069
1554-6578
1554-6578
DOI:10.1093/jnen/nlz110