Scientists Shed Light on Workings of Mutant Alpha-synuclein Protein

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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A mutant form of the alpha-synuclein protein — associated with early onset, severe familial Parkinson’s disease — recruits its normal version to propagate the toxic clumps that lead to neurodegeneration, a study in mice has found.

The data, specific for the E46K mutant version of alpha-synuclein, suggest that the toxic features of this mutant form can be passed on to the healthy version, thereby boosting alpha-synuclein-associated nerve cell death.

These findings shed light on the underlying mechanisms of some cases of  severe familial Parkinson’s, which are characterized by early onset. Further studies are needed to clarify whether the same mechanism applies in other common mutant forms of alpha-synuclein associated with Parkinson’s, the researchers noted.

The study, “Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding,” was published in the journal Proceedings of the National Academy of Sciences.

Nerve cell loss in Parkinson’s disease is mainly triggered by the toxic buildup of misfolded alpha-synuclein clumps, called amyloid fibrils. Alpha-synuclein is a protein abundant in the brain and thought to help regulate nerve cell function and communication.

Heterozygous mutations refer to those present in only one of the two copies of a gene, with the other being healthy. Such mutations in SNCA, the gene that provides the instructions to produce alpha-synuclein, have been linked to the early onset and rapid progression of familial Parkinson’s disease.

A previous study by a team of researchers in China showed that one such mutation, called E46K, results in the production of a smaller alpha-synuclein protein that’s more prone to fragmentation and has higher seeding activity than the normal version of the protein.

Seeding activity is the rate at which a protein clumps together to form toxic aggregates.

However, how this E46K mutant version of alpha-synuclein contributes to early onset and severe familial Parkinson’s disease remains unclear, as does the potential interaction between mutant and healthy forms of the protein and its role in disease progression.

Now, the same team, along with colleagues from other Chinese institutions, provided evidence that the two forms of alpha-synuclein do interact — and in a way that propagates the damaging features of the mutant protein to the healthy version. This potentially accelerates disease progression, according to the researchers.

To learn more, the team had first injected human E46K mutant or healthy alpha-synuclein preformed fibrils into the mice’s brains. They then assessed whether these two forms resulted in differences in clump formation in the brain and in the animals’ motor function.

The results showed that E46K alpha-synuclein fibrils promoted more aggregates or clumps and earlier-onset motor deficits, as compared with human healthy fibrils. Notably, E46K-associated clumps exhibited a distinct structure to those of the healthy version.

Using state-of-the-art technology, the researchers found that E46K mutant alpha-synuclein fibrils were capable of using both human and mouse normal alpha-synuclein molecules to form E46K-like mixed fibrils.

Notably, the human mixed fibrils not only partially replicated the structure and seeding capability of the E46K fibrils but also promoted similar damage, impairing the mice’s motor function at the same early stages.

These findings suggest that E46K mutant alpha-synuclein fibrils “can pass on its structure and pathology [disease-causing features] to the [healthy version], which is not applicable reversely,” the researchers wrote.

This spreading of toxic fibril formation may amplify alpha-synuclein-associated neurodegeneration in familial Parkinson’s, the team noted, adding that other mutated forms of alpha-synuclein may “spread throughout the brain via a similar mechanism.”

“It would be interesting to know whether what we found here is common to other [familial Parkinson’s-related] heterozygous SNCA mutations,” the researchers wrote. The team said future studies are needed to “comprehensively understand” these mutations.

The data also emphasized the importance of fibril structure in alpha-synuclein-associated neurodegeneration and provided insights on the underlying mechanisms of E46K-associated familial Parkinson’s, the team noted.

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