Title: a-synucleïne proteïne aggregatie in synucleinopathieën
Other Titles: A strain on the brain / a-synuclein protein misfolding in synucleinopathies
Authors: Peelaerts, Wouter
Issue Date: 28-Oct-2016
Abstract: Parkinson’s disease, dementia with Lewy Bodies and multiple system atrophy are age-related and devastating neurodegenerative disorders that are characterized by the presence of large proteinaceous clumps of the ɑ-synuclein protein scattered throughout the patient’s central nervous system. The identification of ɑ-synuclein in Lewy bodies made it clear that this protein has a central role in the etiopathogenesis of several age-related neurological diseases. However, today it is still unclear how ɑ-synuclein is involved in the neurodegenerative process and why patients, whose brains are scarred by deposits of a single peculiar protein, present with multiple clinical phenotypes, which we know today as the ‘synucleinopathies’.
Recent studies have shown that ɑ-synuclein can misfold and self-associate into multimeric aggregated structural polymorphs of different sizes and shapes. These aggregated complexes have different biochemical and toxic properties, which has led to the identification of multiple ɑ-synuclein ‘strains’ and the hypothesis that strains could account for the clinical traits observed in synucleinopathy patients. In an experimental setting we have tested the ability of different ɑ-synuclein strains to induce pathology and show that strains are intrinsically pathogenic and have the capacity to induce different synucleinopathies. We furthermore show that pathogenic ɑ-synuclein can spread between connected brain regions and enter the central nervous system from the blood, which might further explain why synucleinopathies are characterized by a progressive disease course.
Protein folding and misfolding is an intricate property of living systems. Understanding how ɑ-synuclein and other proteins misfold is still one of the biggest challenges in neurodegenerative research. This research is amongst the first to provide evidence that variations in the aggregation process of a single protein may be paralleled by the development of multiple neurological diseases. The discovery of strains not only helps us to understand why synucleinopathies are so different, it also holds great promise for our continuous search for new diagnostic tools and therapeutic strategies and raises optimism that someday we will be able to move from a symptomatic to a curative treatment.
Publication status: accepted
KU Leuven publication type: TH
Appears in Collections:Molecular Virology and Gene Therapy
Research Group for Neurobiology and Gene Therapy

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