Study Identifies Distinct Molecular Subtypes of Progressive Supranuclear Palsy

Researchers at the University of Toronto have provided the first evidence that progressive supranuclear palsy (PSP) has distinct molecular subtypes, a finding that points toward tailored treatments for people with this fatal neurodegenerative disease. The findings were published recently in the journal Nature Communications.

The study reveals previously unrecognized heterogeneity in how certain types of tau protein are distributed and active in different brain regions in PSP. These findings suggest that PSP can be subclassified, setting the stage for precision medicine approaches tailored to the molecular underpinnings of this devastating disease.

Progressive supranuclear palsy is a rare but rapidly progressive brain disease caused by misfolding tau protein, which aggregates into clumps and causes brain cells to die. Misfolded tau can cause healthy tau proteins to misfold — a process called seeding — which is primarily how the disease progresses. A similar process happens in Alzheimer's disease.

Like Alzheimer's disease, PSP is a heterogeneous disorder, with patients showing diverse clinical presentations and different patterns of brain involvement; however, the underlying cause of this clinical heterogeneity has remained unknown.

Using tissue from different regions of the brain from people with PSP, researchers found that patients could have varying amounts of high molecular weight (HMW) tau in different brain regions; however, HMW tau was consistently more abundant in brain regions with more damage and less abundant in regions with less damage.

The team then used a specialized assay that can measure how quickly different types of tau protein can convert healthy proteins into misfolded ones. They saw that HMW tau had more seeding capacity than other forms of tau. Patients with more HMW tau are considered "high seeders" who have a more aggressive form of disease.

Researchers saw a very strong correlation between the amount of HMW tau and the amount of seeding. Patients who have tau that aggregates very fast and can convert more healthy protein into misfolded protein have a shorter duration of disease, as the disease progresses faster.

To get insight into how HMW tau has higher seeding capacity, the team studied the molecular pathways affected by HMW tau. They found differences in the molecular pathways in the brain cells of high and low seeding patients, but one of the significant differences between these groups was in immune system pathways: High seeding patients had significant dysregulation of the immune system and more inflammation compared to low seeders — though the researchers don't know yet whether HMW tau causes inflammation or inflammation drives greater seeding capacity.

A multicentre study, supported by the Rainwater Foundation, was recently launched to look for differences in inflammation markers in the blood of different subgroups of people living with PSP to learn more about this association. This result suggests that some patients could benefit from a combination therapy that treats the tau protein and the inflammation.

This new knowledge about the seeding capacity of different patients could help with the design of clinical trials for new therapies. The rare movement disorder affects parts of the brain that control the body's ability to walk and coordinate movement.