Synucleinopathies are caused by a novel mutation.
Because they are caused by the abnormal buildup of protein alpha-synuclein into structures termed Lewy bodies and Lewy neurites in the brain, Parkinson's disease and Lewy body dementia are classified as synucleinopathies.
In a healthy brain, alpha-synuclein is present in synapses as monomers, which are separate proteins. However, different mutations in the alpha-synuclein gene may cause the protein to clump together and form bigger oligomers and even larger fibrils.
Multiple variants of the alpha-synuclein gene that cause synucleinopathies have been found and mapped out, with many studies, including work from the Lashuel lab, indicating that the mutations may function via diverse pathways, resulting in the same disease. Despite their rarity, research into these mutations has yielded crucial insights and assisted in the uncovering of several pathways that contribute to neurodegeneration and the progression of Parkinson's disease.
A brand-new mutation
However, in 2020, a research discovered a novel mutation in the alpha-synuclein gene in a patient with Lewy body dementia and atypical frontal and temporal lobe atrophy. The E83Q mutation replaces the amino acid glutamate (E) with glutamine (Q) at the 83rd position in the protein's amino acid sequence, thus the name. This mutation differs from other other variants in that it is located in the midst of the domain that controls alpha-normal synuclein's activities (interaction with membranes) and initiates aggregation and disease creation.
Taking a different route
"I was interested by the unusual location of this mutation and the fact that the E83Q mutation carrier had significant Lewy body pathology in the cortical and hippocampus areas of the brain rather than the normal substantia nigra," says Hilal Lashuel of EPFL's School of Life Sciences.
"These findings suggested that the new mutation may influence alpha-structure, synuclein's aggregation, and pathogenicity through mechanisms different from those of other mutations," says Lashuel, "and could help us uncover novel mechanisms linking alpha-synuclein to neurodegeneration and pathology formation in Parkinson's disease."
The researchers worked with Markus Zweckstetter's group at DZNE in Germany and Frank Sobott's group at the University of Leeds. They used a variety of biochemical, structural, and imaging techniques to investigate how this mutation affects the structure and aggregation behaviours of alpha-synuclein in vitro. The researchers next employed a variety of cellular models of Lewy body development to see how the E83Q mutation affects different elements of alpha-normal synuclein's function and disease.
Their in vitro investigations revealed that this mutation not only enhanced the rate of alpha-synuclein aggregation considerably, but also produced aggregates with structural and morphological characteristics that differed from the normal protein. "This was intriguing since previous studies have revealed that aggregates of various structures have diverse abilities to produce pathology and disseminate in mice models of PD," says Senthil T. Kumar, one of the study's initial authors.
The researchers compared the ability of E83Q and the normal alpha-synuclein protein to induce pathology formation in a neuronal model of Lew body formation and neurodegeneration that was developed in the Lashuel lab and is widely used to identify novel targets and test new alpha-synuclein targeting therapies to see if these structural differences are sufficient to translate into differences in pathology formation and toxicity.
"The E83Q mutation not only dramatically increased seeding activity and the formation of Lewy body-like inclusions in the neuronal seeding model of Lewy body formation, but it also led to the formation of multiple aggregates with diverse morphological features—very similar to the diversity of alpha-synuclein pathology seen in the brains of Parkinson's disease patients," says Anne-Laure Mahul-Mellier, the study's other first author. "We were ecstatic to discover that we could do it in our Lewy-body in a dish model."
"Our results corroborate alpha-essential synuclein's involvement in the formation of PD and other synucleinopathies, and show that differences in the structural features of alpha-synuclein aggregates may contribute to synucleiniopathies' neuropathological and clinical variability," adds Lashuel. "Thus underscoring the vital need of employing disease models that replicate the variety of human pathology to the greatest degree feasible, as well as medicines capable of addressing the diversity of pathogenic alpha-synuclein species."
In the following phase, Lashuel's team will test their results in animal models using material from the afflicted patient, and they will look into whether this mutation affects alpha-normal synuclein's functions as well.
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