by KU Leuven

Microscopic image of mouse neurons to which the patient-derived
α-synuclein protein was administered. The protein deposits (green)
form after seven days. Credit: Microscopy by Anke Van der Perren

The accumulation of one particular protein in the brain is the basis
of three very different age-related conditions. Until recently, nobody
understood how this was possible. Research by the Laboratory for
Neurobiology and Gene Therapy (KU Leuven) now reveals that the shape
of the protein determines the clinical picture.

The presence of α-synuclein protein deposits in the brain is
characteristic for three different diseases: Parkinson’s disease (PD),
multiple system atrophy (MSA) and dementia with Lewy bodies (DLB).
Although these disorders are part of the same family, they are
clinically and pathologically very different.

Parkinson’s disease affects around two percent of the population over

The condition manifests itself mainly in motor problems. Dementia
with Lewy bodies is less common (0.4 percent of people over 65), but
is still the second most common form of dementia, after Alzheimer’s
disease. Multiple system atrophy is a rare but extremely aggressive
disease for which there is virtually no treatment. It causes a variety
of health issues, including general pain, bladder problems and low
blood pressure, as well as motor problems. Most patients succumb to
the disease within five to ten years.

Simulating disease processes

In collaboration with their colleagues from the French National Centre
for Scientific Research (CNRS) and Imperial College London,
researchers of the KU Leuven Laboratory for Neurobiology and Gene
Therapy isolated the α-synuclein protein from brain tissue of deceased
PD, MSA and DLB patients. This protein was then multiplied and
reproduced with a technique that was specifically designed for this
purpose. The different protein shapes were carefully studied in the
lab and introduced in lab animals to simulate the disease processes.

The researchers were able to identify two shapes of the protein: a
helical one in MSA and Parkinson’s disease, and a cylindrical one in
DLB. The shape also determined the severity of the disease symptoms:
in MSA the symptoms occurred more quickly and aggressively, while in
DLB they were more moderate.

“Previously, it was a mystery why one and the same protein caused
three different brain diseases,” says research coordinator Dr. Anke
Van der Perren. “Now, for the first time, we’ve been able to identify
different shapes of α-synuclein protein deposits in patients.
Depending on the shape, a different disorder and, thus, a different
clinical picture occurs.”

Earlier and better diagnosis

The new insights on the origin and structure of the protein shapes
may, in time, lead to an earlier and better diagnosis, says Professor
Veerle Baekelandt. “To this day, it’s very difficult to diagnose these
three brain disorders. We want to further unravel the complex process
of the protein deposits to gain a better understanding of how the
diseases develop. In time, we hope that we’ll be able to detect these
harmful protein shapes and that a specific treatment can be found to
slow down or even stop the disease process.”

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Explore further

Single protein causes Parkinson’s disease and multiple system atrophy

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More information: Mutated ATP10B increases Parkinson’s disease risk by
compromising lysosomal glucosylceramide export, Acta Neuropathologica
(2020). DOI: 10.1007/s00401-020-02145-7
Provided by KU Leuven