Study finds progressive supranuclear palsy has distinct subtypes, opening door to tailored therapies
A new study from researchers at the University of Toronto has 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.
“Our study reveals previously unrecognized heterogeneity in how certain types of tau protein are distributed and active in different brain regions in PSP, underscoring the complexity of the disease,” said Ivan Martinez-Valbuena, first author on the study and a scientific associate in the lab of Professor Gabor Kovacs at U of T’s Tanz Centre for Research in Neurodegenerative Diseases.
“These findings suggest that PSP can be subclassified, setting the stage for precision medicine approaches tailored to the molecular underpinnings of this devastating disease,” said Martinez-Valbuena, who is also a researcher at the Rossy Progressive Supranuclear Palsy Centre in University Health Network’s Krembil Brain Institute.
The findings were published recently in the journal Nature Communications.
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.
Researchers and clinicians have recognized that Alzheimer’s disease is not a homogeneous disease, and recent evidence suggests differences in disease progression among subtypes is linked to different compositions of misfolded tau. Specifically, high molecular weight (HMW), or larger, tau proteins appear to be more toxic and spread the disease faster than lower-weight tau.
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.
For the current study, Martinez-Valbuena, Kovacs and their colleagues looked at the distribution of misfolded tau and activity in PSP and whether differences in distribution and activity could help categorize subtypes of PSP.
Using tissue from different regions of the brain from people with PSP, they found that patients could have varying amounts of 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.
“We saw a very strong correlation between the amount of HMW tau and the amount of seeding, so we believe that this is clinically meaningful,” said Martinez-Valbuena. “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.
They recently launched a multicentre study, supported by the Rainwater Foundation, to look for differences in inflammation markers in the blood of different subgroups of people living with PSP to learn more about this association.
“Because of the observational nature of our study, we can see there are differences among the groups, though we can’t tell what happened first. This result suggests that some patients could benefit from a combination therapy that treats the tau protein and the inflammation,” said Martinez-Valbuena.
“We know now that inflammation is a big player in Alzheimer’s disease and Parkinson’s, so this evidence of inflammation of PSP adds a new layer of complexity and knowledge that we have to think about when treating these diseases,” he added.
Martinez-Valbuena said this new knowledge about the seeding capacity of different patients could help with the design of clinical trials for new therapies, and that it suggests treating people based on their subtype may be beneficial.
“PSP is not a homogeneous disease, and maybe a drug that doesn’t appear to work in a clinical trial doesn’t have to be discarded and could work in a subset of patients,” Martinez-Valbuena said.
“It’s important to understand why certain patients respond and others don’t. With this understanding, we can find ways to treat subtypes of the disease that target the different molecular mechanisms.”
This study was funded by the Rossy Family Foundation, Edmond J. Safra Philanthropic Foundation, Krembil Foundation, Maybank Foundation, Blidner Family Foundation, Ajay Virmani, Canadian Foundation for Innovation, and the U.S. National Institute Institutes of Health.
