Parkinson’s disease and dementia with Lewy bodies belong to a family of neurodegenerative disorders called synucleinopathies because they are caused by the pathological accumulation of protein alpha-synuclein in structures called Lewy bodies and Lewy neurites in the brain .
In a healthy brain, alpha-synuclein is found in synapses as separate proteins called monomers. But various mutations in the gene that codes for alpha-synuclein can cause the protein to clump together and form larger oligomers and even larger fibrils.
Scientists have identified and mapped numerous mutations in the alpha-synuclein gene that lead to synucleinopathies, with numerous studies, including work from the Lashuel lab, showing that mutations can also act through distinct mechanisms, leading to the same pathology. Although rare, the study of these mutations has yielded important insights and uncovered different mechanisms that contribute to neurodegeneration and the development of Parkinson’s disease.
A new mutation
But in 2020, a study reported a novel alpha-synuclein gene mutation in a patient with dementia with Lewy bodies and atypical frontal and temporal lobe degeneration. The mutation replaces the amino acid glutamate (E) with a glutamine (Q) at 83rd position of the amino acid sequence of the protein – this is why the mutation is called E83Q. What distinguishes this mutation from all previously identified mutations is that it lies in the middle of the domain that regulates the normal functions of alpha-synuclein (interaction with membranes) and drives aggregation and initiation of formation. of pathologies.
Explore a new path
I was intrigued by the unique position of this mutation and the fact that the E83Q mutation carrier showed severe Lewy body pathology in the cortical and hippocampal regions of the brain than the usual substantia nigra which tends to be predominantly affected in Parkinson’s disease.
Hilal Lashuel, EPFL School of Life Sciences
Lashuel adds: “These observations suggest that the new mutation may influence the structure, aggregation, and pathogenicity of alpha-synuclein through mechanisms distinct from those of other mutations and may help us discover new mechanisms linking alpha -synuclein to neurodegeneration and pathology formation in Parkinson’s disease”.
The scientists collaborated with the groups of Markus Zweckstetter at DZNE in Germany and Frank Sobott at the University of Leeds. They applied a battery of biochemical, structural and imaging approaches to dissect how this mutation alters the structure of different forms of alpha-synuclein and its aggregation properties. in vitro. Next, they used a combination of cellular models of Lewy body formation to determine how the E83Q mutation influences various aspects of alpha-synuclein associated with its normal function and pathology.
Their in vitro studies have shown that this mutation not only dramatically increases the rate of alpha-synuclein aggregation, but also forms aggregates with structural and morphological signatures distinct from those seen with the normal protein. “It was exciting since recent studies have shown that aggregates of different structures show differences in their ability to induce pathology and spread in mouse models of PD and could possibly explain the clinical heterogeneity of Parkinson’s disease. and other neurodegenerative diseases,” says Senthil T. Kumar. , one of the first authors of the study.
To determine if these structural differences are sufficient to translate into differences in pathology formation and toxicity, the researchers compared the ability of E83Q and the normal protein alpha-synuclein to induce pathology formation in a neuronal model of Lew body formation and neurodegeneration which was developed in the Lashuel laboratory and is widely used to identify new targets and test new therapies targeting alpha-synuclein.
“In the neural seeding model of Lewy body formation, the E83Q mutation not only dramatically increased seeding activity and the formation of Lewy body-like inclusions, but also led to the formation of multiple aggregates with diverse morphological characteristics – very similar to the diversity of alpha-synuclein pathology seen in the brains of patients with Parkinson’s disease,” explains Anne-Laure Mahul-Mellier, the other first author of the study.”We were delighted to see that we can achieve this in our Lewy-body in a dish model.”
“Our findings support a central role for alpha-synuclein in the development of PD and other synucleinopathies and demonstrate that variations in structural properties of alpha-synuclein aggregates may contribute to neuropathological and clinical heterogeneity in synucleiniopathies. “, says Lashuel. “Thus, underscoring the critical importance of using disease models that replicate the diversity of human pathology as much as possible and therapies that can target the diversity of pathological alpha-synuclein species.”
In a next step, Lashuel’s group will validate these findings in animal models using material isolated from the affected patient, and further investigate whether this mutation also influences normal alpha-synuclein functions.
Federal Polytechnic School of Lausanne (EPFL)
Kumar, ST, et al. (2022) NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity. Scientific advances. doi.org/10.1126/sciadv.abn0044.