Dysfunction of Protein Quality Control in Parkinsonism-Dementia Complex of Guam

Abstract

Guam parkinsonism-dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss. Although both genetic and environmental factors have been implicated, the etiology and pathogenesis of G-PDC remain unknown. Recent neuropathological studies have provided new clues about the pathomechanisms involved in G-PDC. For example, deposition of abnormal components of the protein quality control system in brains of G-PDC patients indicates a role for proteostasis imbalance in the disease. This opens up promising avenues for new research on G-PDC and could have important implications for the study of other neurodegenerative disorders.

Keywords: 43-kDa TAR DNA-binding protein; Guam parkinsonism–dementia complex; mutant ubiquitin; neurofibrillary tangles; neuropathology; protein aggregation; protein quality control; tau.

Figure 1

Neuropathological features of Guam parkinsonism–dementia complex (G-PDC). In the brains of G-PDC patients, various pathological protein aggregates can be found, e.g., neurofibrillary tangles (NFTs) (mouse anti-phosphorylated tau, AT8, 1:3,000, Innogenetics; mouse anti-MC1/CP13, 1:200, gift from Dr. P. Davies) (A,B) and 43-kDa TAR DNA-binding protein (TDP-43)-positive inclusions (mouse anti-TDP-43, 1:1,000, Abnova) (C). Abnormal protein deposits are decorated with ubiquitin (rabbit anti-ubiquitin, Z0458, 1:3,000, DAKO) (D). Immunoreactivity for phosphorylated pancreatic ER kinase (pPERK) indicates activation of the unfolded protein response and is associated with granulovacuolar degeneration (rabbit anti-pPERK, sc-32577, 1:400, Santa Cruz Biotechnology) (E). Furthermore, the ubiquitin-binding protein p62 is deposited in G-PDC brains (rabbit anti-p62, 1:500, Biomol) (F). Accumulation of p62 is a marker for the inhibition of autophagic flux. The photomicrographs in panels (A–F) show representative hippocampal sections from G-PDC brains. Arrowheads indicate distinct immunoreactive structures. Scale bar: 100 µm (Verheijen et al., unpublished data).

Figure 2

Accumulation of mutant ubiquitin (UBB⁺¹) in Guam parkinsonism-dementia complex (G-PDC). UBB⁺¹ is a frameshift mutant of ubiquitin that is generated through “molecular misreading,” a form of transcriptional mutagenesis that introduces dinucleotide deletions (; ΔGA or ΔGU) in or near GAGAG motifs in mRNA (A). UBB⁺¹ contains an extended C-terminal tail that can be recognized by anti-UBB⁺¹ antibodies. Deubiquitinating enzymes (DUBs), i.e., ubiquitin C-terminal hydrolase L3 (UCH-L3), can cleave this abnormal C-terminal domain, destroying the epitope. However, inhibition of DUBs, e.g., by oxidative stress conditions, prevents this cleavage (B). Accumulation of UBB⁺¹ (rabbit anti-UBB⁺¹, Ubi2A, 1:400, Dr. F. W. van Leeuwen) (C) and specific ubiquitin-proteasome pathway components, i.e., the DUB ubiquitin C-terminal hydrolase L1 (UCH-L1) (rabbit anti-UCH-L1, 1:500, Biomol) (D) and the proteasomal ATPase subunit Rpt3 (rabbit anti-Rpt3, 1:400, Biomol) (E) can be observed in G-PDC patient brains (hippocampal sections), which strongly suggests proteostasis breakdown. UBB⁺¹ is not present in young control brains (non-Guamanian cases). Arrowheads indicate various immunoreactive structures. Scale bar: 100 µm (Verheijen et al., unpublished data).