Researchers at UT Southwestern Medical Center contribute to the growing investigations into the causes of progressive supranuclear palsy (PSP) and effective ways to treat – and even cure – this rare disorder.
PSP affects approximately 1 person out of 10,000 in the general population. But until 1963, it was not recognized as a unique condition. Three researchers – 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 PSP has focused on several areas:
Studying the Patterns
Investigating populations in which PSP occurs could help identify reversible risk factors.
PSP is present in all populations, but certain places and people appear to have an elevated risk and similar environmental conditions. Medical experts suspect that organic chemicals such as pesticides can predispose patients to PSP, but this is not proven.
A neurodegenerative syndrome similar to PSP is found at high prevalence on the island of Guam, leading to the hypothesis that an environmental factor is responsible. Some patients with 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.
PSP Genetics
While PSP is not an inherited disorder, the genetic background of patients with PSP plays into the risk of developing the illness.
While other genes likely influence a person’s risk for PSP, most of the current 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 or four times, depending on the individual. Having four repeats must predispose a person to developing PSP because everyone with PSP has four repeats. On the other hand, many people have four repeats and never develop any neurological degeneration.
Tangles in the Brain
Under the light microscope, brain tissue from a patient with PSP shows thinning and loss of neurons, particularly in 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.
Molecular Misshaping
Each neuron, like every cell, is continually building and recycling thousands of different types of proteins. 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 tau proteins can influence neighboring tau proteins to adopt their same shape, like templating.
In certain shapes, tau can be difficult for the cell to digest and recycle. The misshapen tau then accumulates, leading to further templating of misshapen tau, which can spread from one neuron to the next adjacent one, damaging these neurons like a slow-burning 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.
Preventing Progression
The recent recognition of the buildup of misshapen tau 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, which could 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 we are at the stage of planning cautious test studies in humans. In addition, test programs for specific small molecules target a step in the cascading disruption that follows the tau accumulation.
Finding a Cure
If interventions such as those described above prove effective and safe, then we could 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.
