Different strains of misfolded α-synuclein (α-syn) can cause clinically and pathologically distinct diseases in mice, according to a new study published in Nature Neuroscience. The findings highlight similarities between synucleinopathies and prion disease.

Synucleinopathies are neurodegenerative diseases that are characterized by the misfolding and aggregation of α-syn in the brain. These diseases have different clinical and pathological features, although the reasons for the differences are unclear.

The misfolding of prion protein (PrP) also causes neurodegenerative disease. Misfolded PrP induces misfolding of healthy PrP, enabling the prion pathology to spread. Distinct conformational strains of PrP cause distinct diseases that can be transmitted between individuals by transfer of the misfolded protein. The new study, led by Joel Watts, aimed to establish whether different conformational forms of α-syn can behave like strains of PrP and are responsible for different synucleinopathies.

The researchers generated two conformational strains of misfolded α-syn, called ‘S’ and ‘NS’. Both strains produced α-syn pathology and neurological illness when injected into mice that expressed a mutant form of human α-syn. Injection of properly folded α-syn did not induce pathology in these mice. Importantly, the diseases induced by the two strains of α-syn differed in their incubation periods, clinical signs and in the brain regions and cell types affected by α-syn pathology.

the diseases induced by the two strains of α-syn differed

Extracts from the brains of mice treated with the S or NS strains induced disease when injected into a second set of mice. Furthermore, when brain extracts from this second set of mice were injected into a third set of mice, the differences between the diseases caused by the N and NS strains were maintained.

“This observation means that strain-specific information is encoded within the structure of the α-syn aggregates and can be transmitted from cell to cell and mouse to mouse in a ‘prion-like’ fashion,” explains Watts.

The findings suggest that different synucleinopathies are caused by distinct strains of misfolded α-syn, but further work is needed to confirm this hypothesis. “It is likely that the α-syn strains we have uncovered so far will only partially mimic human synucleinopathies, so it will be important to continue to search for additional strains,” concludes Watts.