Selective insolubility of alpha-Synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model

alpha -Synuclein (alpha -SYN) is deposited in intraneuronal cytoplasmic inc lusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha -SYN forms LB-like fibrils in vitro, in contrast to its homologue beta -SYN. Here we have investigated the solubility of SYNs in h uman LB diseases and in transgenic mice expressing human wild-type and PD-a ssociated mutant [A30P]alpha -SYN driven by the brain neuron-specific promo ter, Thy1. Distinct alpha -SYN species were detected in the detergent-insol uble fractions from brains of patients with PD, dementia with LBs, and neur odegeneration with brain iron accumulation type 1 (formerly known as Haller vorden-Spatz disease). Using the same extraction method, detergent-insolubi lity of human alpha -SYN was observed in brains of transgenic mice. In cont rast, neither endogenous mouse alpha -SYN nor beta -SYN were detected in de tergent-insoluble fractions from transgenic mouse brains. The nonamyloidoge nic beta -SYN was incapable of forming insoluble fibrils because amino acid s 73 to 83 in the central region of alpha -SYN are absent in beta -SYN. In conclusion, the specific accumulation of detergent-insoluble alpha -SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.