Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that causes atypical progressive and fatal parkinsonism. PSP usually manifests itself when people are in their 60s, with a median survival of only 7 years. The clinical presentation of PSP includes severe gait instability with frequent falls, slowing of vertical eye movements that progresses to a supranuclear restriction of gaze, slowed movement, rigidity of the musculature, difficulties with swallowing, and cognitive decline. Genetic associations with PSP have so far been attributed mainly to changes in the gene that codes for the microtubule-associate tau protein. This protein is very important for adequate signaling by nerve cells. A critical role for tau in the disease process is further supported by the strong link between PSP and the presence of insoluble aggregates of abnormal tau protein in various areas of the brain. The prevalence of PSP in Europe and the US is between 5 and 6 per 100,000, making it an orphan disease.

PSP belongs to the groups of neurodegenerative disorders referred to as ‘tauopathies’. In such disorders, tau protein becomes hyperphosphorylated, due at least in part to chronic oxidative stress. This ultimately leads to the accumulation of insoluble aggregates of tau protein. Inside neurons, this frustrates the normal role of tau, which is to control transport of signaling substances along nerve tracts. Tau protein also accumulates outside cells. Such deposits can be directly toxic to neurons, and additionally trigger chronic pro-inflammatory responses by microglia that ultimately lead to neuronal death. These events can be mimicked in mouse models by the introduction of mutated tau genes. To date, no effective therapy for PSP is available. Symptomatic treatment is the only option, with medication to improve balance and ameliorate stiffness, to counteract depression, and to treat pain and sleeping problems in PSP.

Deposit of abnormal tau protein in brain tissue during PSP