Cryo-EM structures of filaments from the brains of individuals with variants G51D and H50Q in α-synuclein

Gene dosage and point mutations in SNCA , the a-synuclein gene, give rise to familial forms of Parkinson’s disease and dementia with Lewy bodies; an insertion mutation in SNCA causes juvenile-onset synucleinopathy. We previously reported the electron cryo-microscopy (cryo-EM) structures of a-synuclein filaments from the brains of individuals with Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, as well as from the brain of an individual with juvenile-onset synucleinopathy. Here we report the cryo-EM structures of a-synuclein filaments from the frontal cortex of two cases with Parkinsonism and mutation G51D in a-synuclein and those from the amygdala of a case with Parkinson’s disease and variant H50Q in a-synuclein. The G51D filaments of assembled a-synuclein consist of two identical protofilaments with the Lewy fold and island B, but without the previously identified disconnected density island A. The protofilament interface is made of residues E46, V48 and H50. Filaments with the H50Q variant comprise a single protofilament with the Lewy fold and both islands A and B. Unlike G51D, the pathogenicity of H50Q has been questioned. It remains to be seen if dimerisation of the Lewy fold may also underlie the pathogenicity of other missense mutations in a-synuclein. Moreover, filaments with a single Lewy fold have a right-handed helical twist, while the G51D, multiple system atrophy and juvenile-onset synucleinopathy filaments are left-handed, which may also be significant.