Tau is a microtubule-associated protein, normally binding to tubulin, in an interaction mediated by chaperones. Unwanted tau is degraded by proteasomes. The tauopathies are neurodegenerative disorders characterized by a tau-predominant neuropathology. Tauopathies include Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17, which can be caused by mutations in the tau gene). Pathological tau is hyperphosphorylated, and has reduced microtubule binding capacity. Tau mutations in the microtubule-binding region have similar effects. In some tauopathies, tau deposition is isoform-specific, and pathogenic mutations can cause isoform imbalances. Oxidative stress may also be a factor in tauopathies. In addition, tau pathology has been associated with an ubiquitin variant, which causes proteasome inhibition. There is evidence of aberrations in the chaperone system in diseased cells, reducing tau-microtubule binding, and degradation. To investigate the role of UBB+1 in tauopathies, a model system was developed with SH-SY5Y neuroblastoma cells, which showed that UBB+1 inhibits the proteasome. UBB+1 expression did not affect tau, but was coupled with a chaperone expression response. Subsequently, contrary to expectations, cells with induced UBB+1 expression coped better with oxidative insults. These proteins were studied in sections from PSP brains; UBB+1 and abnormal tau were only present in the diseased tissue. Chaperones and UBB+1 did not co-localise, indicating a failure in the chaperone response. In cells, mutant-tau localized with microtubules as effectively as wild-type. Through neuronal differentiation, tau concentrations were greatly increased, and phosphorylation was decreased. Proteasome inhibition did not increase tau concentration or phosphorylation, or affect isoform balance. A failure in the chaperone response in the brains of tauopathies could explain an increase in unbound cytosolic-tau, tau aggregation, decreased proteasome activity, and susceptibility to oxidative stress.