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Alpha‐synuclein inoculation initiates a neurodegenerative cascade in nontransgenic mice

Several neurodegenerative diseases, including Parkinson’s disease (PD), are characterized by abnormal accumulation of misfolded proteins. In PD, alpha-synuclein (a-Syn) is one of the major components of the intraneuronal proteinaceous inclusions called Lewy bodies (LBs). However, a clear relationship between a-Syn accumulation and neurodegeneration remains unclear. Back in 2008, two groups suggested that a-Syn has prion-like properties because LBs form in fetal grafted dopaminergic neurons in the brain of PD patients, leading to the “host to graft” hypothesis. Consequently, evidence has emerged reinforcing the prion-like hypothesis and the toxicity of a-Syn aggregates. In the past two years, a group led by Virginia Lee has shown that synthetic a-Syn preformed fibrils (PFFs) are able to accelerate the onset of pathology in a mouse model overexpressing mutant human a-Syn and to corrupt endogenous a-Syn in primary neuronal cultures from wild-type (WT) mice, suggesting that LB transmission might occur in WT mice in vivo. The article published in Science by the same group tested this hypothesis by unilaterally injecting PFFs in the dorsal striatum of WT mice. Luk et al. observed that 30 to 180 days postinjection, deposits of hyperphosphorylated a-Syn (a marker of human LBs) were present in several areas connected to the striatum with a time-dependentaccumulation. The observed LB-like inclusions shared common features with LBs of human pathology because they colocalized with key histological markers, such as ubiquitin, heat-shock protein 90, and the amyloid-binding dye, thioflavine S. a-Syn pathology induced by PFFs, but not monomeric a-Syn, was accompanied by a progressive loss (up to 27.7%) of dopaminergic neurons in the SNpc, but not in the adjacent dopaminergic region (the ventral tegmental area). Concomitant with the loss of neurons, researchers observed a reduction in dopamine levels in the striatum and several motor impairments revealed by rotarod and wire hang tests (measuring coordination, balance, and motor strength). This work elegantly showed that a single injection of synthetic misfolded a-Syn was able to initiate a cascade of events leading to LB-like inclusions, selective loss of neurons in the SNpc, and motor impairments, suggesting that a-Syn pathology might be sufficient to induce the cardinal features of PD. Further work should use pathologic a-Syn aggregates, rather than artificial fibrils. Hopefully, this new model will help to determine the deleterious cascade leading to the onset of PD pathology.