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.
