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 (UBBthorn1), whose presence is a marker for UPS dysfunction, is shown to accumulate in G-PD brains. We demonstrate that UBBthorn1 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 language | English |
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Pages (from-to) | 34-45 |
Number of pages | 12 |
Journal | Journal of Neuropathology and Experimental Neurology |
Volume | 79 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jan 2020 |
Keywords
- accumulation
- alzheimers-disease
- amyotrophic-lateral-sclerosis
- autophagy
- complex
- endemic disease
- endoplasmic reticulum stress
- endoplasmic-reticulum
- guam parkinsonism-dementia
- mutant ubiquitin
- neurodegenerative diseases
- tauopathy
- tdp-43
- ubiquitin-proteasome system
- unfolded protein response
- UBIQUITIN-PROTEASOME SYSTEM
- Mutant ubiquitin
- ALZHEIMERS-DISEASE
- Autophagy
- NEURODEGENERATIVE DISEASES
- Endoplasmic reticulum stress
- Guam parkinsonism-dementia
- Unfolded protein response
- MUTANT UBIQUITIN
- ENDEMIC DISEASE
- COMPLEX
- AMYOTROPHIC-LATERAL-SCLEROSIS
- AUTOPHAGY
- Tauopathy
- TDP-43
- ENDOPLASMIC-RETICULUM
- ACCUMULATION
- Ubiquitin-proteasome system