Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains a-, b-, and g-synuclein

Pathogenic a-synuclein (aS) gene mutations occur in rare familial Parkinson’s disease (PD) kindreds, and wild-type aS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer’s disease, but b-synuclein (bS) and g-synuclein (gS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to aS and bS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2y3 regions, whereas antibodies to gS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the aSand bS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative ‘‘synucleinopathies’’ by implicating bS and gS, in addition to aS, in the onsetyprogression of PD and DLB.