LAUSR

α-Synucleinopathies are a heterogeneous group of progressive neurodegenerative disorders characterized by the presence of α-synuclein aggregates and include Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA). In disease, α-synuclein is believed to play a pathogenic role and may self-propagate in a prion-like fashion: a misfolded prion protein (PrP) triggering conformational conversion of normally folded PrP into misfolded forms. Like the different PrP strains, α-synuclein aggregates have been shown to exhibit strain-like behavior, including variable capacities to spread and induce neurotoxicity. Indeed, α-synuclein aggregates from patients with different α-synucleinopathies have revealed distinct seeding activities, for example, MSA-derived α-synuclein aggregates were found to be more robust inducers of neuropathology than PD-derived aggregates. Although the current literature supports the existence of α-synuclein strains, it remained unclear whether the different strains may exhibit important hallmarks of prion strains, including the ability to induce distinct, serially transmissible disease. This question was explored by Lau and colleagues, as discussed below. First, 2 α-synuclein fibril strains were generated via the polymerization of A53T-mutant α-synuclein in the presence and absence of NaCl, named salt (S) and no-salt (NS) fibrils, respectively. The NS fibrils were experimentally determined to be longer and more stable than the S fibrils and developed “thread-like” aggregates in cultured cells, whereas “globular” inclusions were observed with S fibrils. Then, the pathological properties of these conformationally distinct strains were investigated through intracerebral inoculation in transgenic hemizygous TgM83 mice that overexpress A53T-mutant α-synuclein. Mice inoculated with NS fibrils took longer to develop disease versus those inoculated with S fibrils. Further experiments indicated a reduced fragmentation rate and comparatively greater conformational stability associated with the NS strain. Clinical signs indicative of neurological illness were distinct: weight loss, mild kyphosis, and a hindlimb shaking phenotype were evident in NS fibril-inoculated mice, whereas partial or complete hind-limb paralysis with bradykinesia was predominant in those with S fibril inoculation. The former group also showed abundant phosphorylated α-synuclein (PSyn) deposits in the cortex, hippocampus, and olfactory bulb, whereas PSyn pathology was absent in the hippocampus in S fibril-inoculated mice, suggesting strain-specific regional involvement. In regions affected by both strains, the morphology and cellular vulnerability associated with PSyn aggregates varied between the strains. Specifically, TgM83 mice injected with S fibrils displayed “ring-like” PSyn inclusions within neurons, similar to those shown in atypical MSA patients. Conversely, mice injected with NS fibrils not only had “Lewy body-like” intraneuronal pathology, but in addition showed PSyn staining within astrocytes (unlike oligodendroglial pathology characteristic of MSA). Indeed, the S and NS strain-specific findings were maintained on serial passaging and mirrored those observed using MSA-derived and TgM83-derived α-synuclein strains, respectively. The study highlights that, like the PrP strains, different α-synuclein strains may result in distinct phenotypes and may underlie the clinical and pathological heterogeneity evident in human α-synucleinopathies. Among the study’s limitations include difficulties in extrapolating findings from transgenic animal models in describing human pathologies, utilization of a relatively small sample size, and employment of an artificial method to generate α-synuclein strains, which is unlikely to explain their genesis in vivo. It is also worth noting that neither fibril strain induced the oligodendroglial pathology that typifies classic MSA. Future research characterizing the human α-synuclein strains may ultimately facilitate the development of strain-specific personalized therapies for patients.