A detailed analysis of alpha-synuclein — a key protein involved in Parkinson’s — revealed how variants of this protein change over time, allowing researchers to identify the initial stages of protein aggregation involved in early onset disease.
These findings provide new insights into how genetic mutations — especially the point mutation A53T — can contribute to familial Parkinson’s, and into understanding why this disease form manifests earlier and is often more severe than sporadic (of unknown cause) Parkinson’s.
The study, “Alpha-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson’s disease,” was published in the journal Communications Biology.
Parkinson’s is largely a sporadic disease, with 15% to 25% of all cases linked to inherited genetic mutations. One of the first genes identified as directly associated with Parkinson’s, leading to early onset disease, was the alpha-synuclein coding gene SNCA.
It is widely accepted that alpha-synuclein is an important element that drives nerve cell death across several human neurodegenerative disorders, including Parkinson’s and dementia with Lewy bodies. Its toxic effect is, at least in part, tied to the formation of abnormal protein aggregates or clumps.
Despite available knowledge of the damaging impact alpha-synuclein clumps have on nerve cells, the process by which alpha-synuclein changes from a single protein structure into an aggregate form remains poorly understood.
Researchers at the Federal University of Rio de Janeiro (UFRJ) in Brazil conducted a series of biochemical, kinetic, and structural studies to address this gap.
They evaluated in detail the behavior of alpha-synuclein — both its normal form as well as mutated versions found in people with familial Parkinson’s — and its ability to form toxic clumps.
“The conversion from one protein stage to the other takes place slowly. The intermediate structures and the amyloid aggregates accumulate over time in the brain. So far, we don’t know which species cause the symptoms and toxicity to cells,” Guilherme A. P. de Oliveira, a professor at UFRJ and the study’s lead author, said in a press release.
“If we understand the protein species forming during the early stages of disease conversion, we can propose new therapies for disease detection before the symptoms appear.”
Results showed that the versions of alpha-synuclein carrying A53T, A30P, or E46K point mutations were able to from small aggregates (known as oligomers) at a much faster rate than a normal version of the protein.
Of note, point mutations are genetic alterations where a single nucleotide — the building blocks of DNA — is changed, inserted, or deleted from a sequence of DNA. If you think of DNA as a Lego train, a point mutation would be the same as changing, adding, or taking out a single piece.
Next, the researchers used cutting-edge imaging techniques to visualize for the first time, in detail and over time, all the elements involved in the expansion of alpha-synuclein aggregates — their transition from early oligomers to intermediate fibrils to late filaments.
“By (…) acquiring advanced electron microscope images, we are able to better understand these wrong protein associations in their native environment and [potentially find] ways to avoid their formation,” Oliveira said.
This approach showed that the different protein versions give rise to structurally different fibrils.
The expansion of fibrils into long filaments was found to be dependent on the ability of alpha-synuclein to continue to recruit available oligomers.
Interestingly, the A53T point mutated version was able to overcome some of the limits on protein clumping imposed by the surrounding environment, and for which normal alpha-synuclein showed a sensitivity. This suggests that A53T mutations give alpha-synuclein a greater potential to promote aggregation and induce faster spreading of its toxic clumps.
“Our findings place A53T with features that may explain the early onset of familial Parkinson’s disease cases bearing this mutation,” the researchers concluded.
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