Progressive Supranuclear Palsy Research

History of Understanding of PSP

PSP may have affected humans throughout all of human history at roughly the same prevalence (adjusting for age structure of populations) at which it currently does. However, prior to 1963, it was not recognized as a unique condition. Instead, patients with PSP were presumably misdiagnosed as having another neurologic condition. Steele, Richardson, and Olszewski published the original report of a group of patients with the profile we now recognize as PSP, and the condition is sometimes named in their honor. Research into the clinical course followed, as well as analysis of brain tissue and genetic analysis. PSP was recognized to be a tauopathy, with disordered aggregation of tau protein in neurons as the likely cause of neuronal loss. Our understanding is accelerating regarding the processes leading to the aggregation and spread of tau.

Epidemiology of PSP

PSP affects approximately 1 person out of 10,000 in the general population. Investigating populations in whom PSP occurs has been an active area of research, in the hope of identifying reversible risk factors in affected “clusters”. PSP is present in all populations, but there are places and people that appear to have an elevated risk and similar conditions. A neurodegenerative syndrome similar to PSP is found at high prevalence on the island of Guam, leading to hypothesis that an environmental factor is responsible. Some patients suffering from Guamanian neurodegeneration are indistinguishable from patients with PSP, whereas other patients look more like people with dementia or amyotrophic lateral sclerosis (ALS). The clustering in this island has provoked hypotheses that the neurodegeneration is caused by a local toxin (for example a neurotoxin found in an indigenous fruit) or genetic idiosyncrasies which could be enriched locally. There has been suspicion that organic chemicals such as pesticides can predispose patients to PSP, but this is not proven.

PSP Genetics

While PSP is not predictably transmitted within families in the manner of hemophilia, the genetic background of the individual plays into the risk of developing the neurodegeneration. While other genes likely influence the risk, most of the research and evidence focuses on the tau gene. This gene, which codes for tau protein, is located on chromosome No. 17. A common variation of this chromosome called the H1 haplotype, which is present in approximately two-thirds of all humans is found in essentially everyone with PSP. The tau gene itself contains a “repeat domain,” a sequence that is repeated three times of four times, depending on the individual (or more accurately, on each of a person’s two copies of chromosome No. 17). Having four repeats must predispose a person to developing PSP, because everyone with PSP has four repeats. On the other hand, very many people have four repeats and never develop any neurological degeneration.

Histopathology of PSP

Under the light microscope, brain tissue from a patient with PSP shows thinning and loss of neurons particularly in the region of the midbrain, but also in the deep nuclei of the brain such as the globus pallidus. Surviving neurons can manifest aggregations sometimes called neurofibrillary tangles. In combination with other features typical of PSP, these findings are used to make a pathologically confirmed diagnosis of PSP. 

PSP at a Molecular Level

Each neuron, like every cell, is continually building and recycling thousands of different types of proteins, and these proteins perform the many functions undertaken by the cell. Tau is one such protein, whose function relates to the structural scaffolding and shaping of the cell. Tau can take a number of different 3-D shapes, depending on factors such as chemical environment, and also the shape of other tau proteins in the neighborhood which can influence a protein to adopt the same shape, like templating. In certain shapes, tau can be difficult for the cell to digest and recycle. The mis-shapen tau accumulates leading to further templating of mis-shapen tau, which can spread from one neuron to the next adjacent one, damaging these neurons like a slow burning forest fire. It is not yet understood why particular neurons in the midbrain which are important for eye control and balance are selectively vulnerable to this disease process.

Prospects for Preventing Progression of the PSP Pathogenesis

With the recent recognition that misfolded tau accumulates, provoking misfolding and further accumulation of additional tau molecules, has opened the door to interventions to clear the abnormal tau or mitigate its accumulation. Two of the techniques being actively investigated are infusions of antibodies against tau to capture and mobilize the protein for excretion and anti-aggregation molecules that interfere with tau accumulation in neurons. These types of interventions have shown promise in the lab and in animal models, and are at the stage of planning cautious test studies in humans. In addition, there are test programs for specific small molecules which target one or other step in the cascading disruption which appears to follow the tau accumulation.

Prospects for Neuronal Replenishment and Disease Reversal

If interventions such as those described above prove effective and safe, then we may be close to being able to stop the disease from progressing, or at least substantially slow it down. The task of replacing injured and lost neurons, and recovering their functions, is a substantially difficult task. The technology is not yet mastered for replacing the correct type of neurons, integrating such new cells into the network, and controlling their activity to perform the normal tasks.