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

Bert M Verheijen, Celina Lussier, Cora Müller-Hübers, Ralph M Garruto, Kiyomitsu Oyanagi, Ralf J Braun, Fred W van Leeuwen

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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.

Original languageEnglish
Pages (from-to)34-45
JournalJournal of Neuropathology & Experimental Neurology
Volume79
DOIs
Publication statusPublished - 2020

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Verheijen, B. M., Lussier, C., Müller-Hübers, C., Garruto, R. M., Oyanagi, K., Braun, R. J., & van Leeuwen, F. W. (2020). Activation of the Unfolded Protein Response and Proteostasis Disturbance in Parkinsonism-Dementia of Guam. Journal of Neuropathology & Experimental Neurology, 79, 34-45. https://doi.org/10.1093/jnen/nlz110