The synucleinopathies are a group of neurodegenerative
diseases, all characterized by an abnormal accumulation of aggregates of a protein
called alpha-synuclein. The group included such pathologies as Parkinson's
disease, Lewy body dementia and multiple system atrophy.
In an international study carried out in partnership
with the University of Louvain and Imperial College London, researchers from
the Laboratory of Neurodegenerative Diseases (MIRCen/CEA-Jacob) showed that
aggregates from any one synucleinopathy differ molecularly from those of
another. The aggregates present thus differentiating, molecular
"fingerprints," so to speak.
The team used an in vitro protein misfolding cyclic
amplification approach on homogenates of brain tissue from deceased
synucleinopathy patients to characterize the properties of alpha-synuclein
aggregate strains in disease and compare them to pure in vitro alpha-synuclein
assemblies.
They also studied the abilities of the different
strains to provoke the characteristic symptoms of each synucleinopathy in a
murine model. Some of the strains caused rapid and others slow disease
progression, always with distinct inflammatory responses. Thus, in a manner
similar to viral infection, the disease, its progression and the brain regions
it affects are dependent on the structural properties of the alpha-synuclein
aggregates.
The alpha-synuclein aggregates
present in the brains of deceased patients who had Parkinson's disease, Lewy
body dementia or multiple system atrophy were used to seed and template in
vitro alpha-synuclein. With that approach, the team was able to show that the
strains were biochemically distinct. As seen in the electron microscopy images
presented here, the characteristic aggregates of Parkinson's disease (PD),
dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are
dissimilar (black bar = 100 nanometers (one millionth of a meter)). The team's
amplification approach produced sufficient alpha-synuclein aggregates to test
their pathogenic properties in a murine model.
© Luc Bousset
The study's results establish a robust molecular basis
for the identification of synucleinopathies and for better pathophysiological
characterizations of them. The distinct strains of alpha-synuclein aggregates
would appear to correlate with the clinical presentations of their respective
synucleinopathies.
The development of techniques to specifically detect
the differentiating molecular fingerprint of each aggregate strain may
contribute to an earlier and more precise diagnosis of disease. The work done
by this international team widens the range of possibilities in the
identification of therapeutic strategies for Parkinson's disease, Lewy body
dementia and multiple system atrophy.