Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein

Pathogenic alpha-synuclein (alpha S) gene mutations occur in rare familial Parkinson's disease (PD) kindreds, and wild-type alpha S is a major compone nt of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease, but beta-synuclein (beta s) and gamma-synu clein (gamma S) have not yet been implicated in neurological disorders. Her e we show that in PD and DLB, but not normal brains, antibodies to alpha S and beta S reveal novel presynaptic axon terminal pathology in the hippocam pal dentate, hilar, and CA2/3 regions, whereas antibodies to gamma S detect previously unrecognized axonal spheroid-like lesions in the hippocampal de ntate molecular layer. The aggregation of other synaptic proteins and synap tic vesicle-like structures in the alpha S- and beta S-labeled hilar dystro phic neurites suggests that synaptic dysfunction may result from these lesi ons. Our findings broaden the concept of neurodegenerative "synucleinopathi es'' by implicating beta S and gamma S, in addition to alpha S, in the onse t/progression of PD and DLB.