Fig 1.
The rate of disease progression is strain specific.
The time required for a patient to become symptomatic is determined by the energy required for each α-synuclein monomer to adopt a particular misfolded conformation (MSA shown in blue and PD shown in red). Notably, spreading of misfolded α-synuclein occurs during both the prodromal and symptomatic periods of disease. Cryo-electron microscopy studies have shown that α-synuclein misfolds into 2 heterotypic protofilaments in MSA, which grow to form a distinct twisting filament (PDB ID: 6XYO). By comparison, the single protofilament of PD leads to the formation of a filament with minimal twist (PDB ID: 8A9L). Figure was created with BioRender.com.
Fig 2.
Distinct α-synuclein strains exhibit unique biological activities.
(Top) Misfolded α-synuclein fibrils isolated from PD (left) and MSA (right) patient samples adopt distinct conformations. PD fibrils (PDB ID: 8A9L) are shown in blue and MSA fibrils (PDB ID: 6XYO) are shown in teal. (Middle) Each α-synuclein strain gives rise to a distinct neuropathological hallmark in the brain. PD patients develop neuronal LBs (left), whereas MSA patients develop glial cytoplasmic inclusions in oligodendrocytes (right). Scale bar, 50 μm. (Bottom) The 2 α-synuclein strains have opposite biological effects when transmitted to 2 research models. TgM83+/− mice expressing human α-synuclein with the A53T mutation remain asymptomatic >500 dpi when inoculated intracranially with PD patient samples. TgM83+/− mice inoculated with MSA patient samples develop neurological disease in approximately 120 dpi. Similarly, α-synuclein prions isolated from PD patient samples are unable to replicate in HEK293T cells expressing YFP-tagged α-synuclein with the A53T mutation; however, α-synuclein prions isolated from MSA patient samples easily replicate and induce YFP-positive puncta in the cells. Figure was created with BioRender.com. dpi, days postinoculation; LB, Lewy body; MSA, multiple system atrophy; PD, Parkinson’s disease; YFP, yellow fluorescent protein.