Deposition of mutant ubiquitin in parkinsonism–dementia complex of Guam

Guam parkinsonism–dementia complex (G-PDC) is an enigmatic neurodegenerative disease that affects the Chamorro residents of the Pacific island of Guam. G-PDC is clinically characterized by progressive cognitive impairment with extrapyramidal signs. Pronounced loss of neurons and abundant neurofibrillary tangles (NFTs) are observed throughout the brain of G-PDC patients [6, 7]. Although several hypotheses have been suggested for the cause of G-PDC, notably genetic predisposition and exposure to neurotoxins (e.g., β-N-methylamino-L-alanine (BMAA)), the etiology and pathogenesis remain elusive [10]. A frameshift mutant of ubiquitin, known as ubiquitinB (UBB), was previously found to accumulate in the neuropathological hallmarks of Alzheimer’s disease and several other disorders, including tauopathies and polyglutamine diseases [1, 3, 12] (Fig. 1a-b). UBB is a dosedependent inhibitor of the ubiquitin-proteasome system (UPS) and its accumulation in cells an indicator of protein quality control failure. Impaired protein homeostasis is a frequent feature of neurodegenerative diseases and we hypothesized that accumulation of UBB might also be observed in G-PDC. To test whether UBB is detectable in G-PDC brains, immunohistochemical analyses were performed on G-PDC post-mortem brain tissue (Table 1). Immunohistochemistry confirmed the presence of numerous NFTs in G-PDC brains [5] (not shown), as well as other pathology that has been described to occur in G-PDC, i.e., TAR DNA-binding protein 43 (TDP-43)-positive inclusions [5] (Fig. 1f-h). Importantly, our results show that UBB is present in GPDC brains. UBB deposits were found specifically in cytoplasm of pyramidal neurons and glia (astrocytes in the alveus and stratum oriens) in Ammon’s horn, showing a granular and tangle-like pattern of distribution (Fig. 1c-e). UBB was not detected in young control brains (n = 2, non-Guamanian cases, ages: 52 and 59 years old) [8]. Aggregate structures containing distinct components of the UPS, i.e., the deubiquitinating enzyme (DUB) ubiquitin C-terminal hydrolase L1 (UCH-L1) [9] (Fig. 1i-k) and the proteasomal ATPase subunit Rpt3/S6b [13] (Fig. 1l-n), were also present in these brains. This demonstration of UBB-immunoreactivity and accumulation of particular UPS components in G-PDC brains (n = 6) might have important implications for understanding of the pathological mechanisms underlying the disease. UBB has previously been shown to induce neuronal defects in in vitro and in vivo experimental models: long-term UPS inhibition due to UBB expression causes memory deficits and central breathing dysfunction in mice [4, 8, 11]. In addition, UBB might act as a modifier of other pathology in G-PDC. For example, UBB may enhance the aggregation and cellular toxicity of the RNA-binding protein TDP-43 through interfering with its degradation. It is striking that UBB accumulates in glial cells in G-PDC, because similar glial inclusions have been reported in progressive supranuclear palsy (PSP) [3], a disease that displays some similar topography of neurofibrillary degeneration [10]. Recognition of common mechanistic themes shared by neurodegenerative disorders, such as dysfunctional (ubiquitin-dependent) protein degradation and proteotoxic stress, may help in identifying therapeutic targets that prevent neurodegeneration. It will be interesting to investigate the potential contribution of disrupted proteostasis and UBB to G-PDC in more detail in future studies. * Correspondence: [email protected] Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands Full list of author information is available at the end of the article