Table 1.

Evidences supporting the existence of distinct strains in classical α-synucleinopathies and limitations of the current studies.

	Current knowledge	Limitations of current studies
Toxicity in vitro/in vivo	PD, DLB and MSA α-syn strains are able to induce neurological deficits or neurodegeneration in vitro or in vivo. However, MSA-derived fibrils seem to have a stronger toxic potential (61, 72–74, 83).	• Use of different in vivo and in vitro models between studies. • Use of different genetic backgrounds (overexpression of WT or mutant forms of α-syn VS non-transgenic models).
Aggregation potential	PD, DLB and MSA α-syn strains are able to induce aggregation of endogenous α-syn in vitro and in vivo with MSA-derived α-syn showing higher aggregation potential (74–78, 83).	• Use of different sources of human α-syn (brain regions, age, sex, α-syn content).
Biochemical properties	MSA, PD and DLB strains present different proteinase K resistance and sarkosyl solubility patterns with MSA fibrils showing the highest resistance to protein degradation and DLB – the lowest (77, 78, 81, 83).	• Use of non-standardized protocols among studies or different experimental techniques.
Structural differences	MSA and PD fibrils exhibit twisted appearance, with MSA fibrils shoing higher twist frequency than PD fibrils. DLB fibrils are predominantly thinner with no twists (77, 81–83).	• Small number of cases included. • Limited number of studies including all α-synucleinopathies.
Amplification kinetics	MSA strains exhibit different amplification kinetics compared to PD and DLB strains in PMCA and RT-QuIC studies (99–101).