Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy

The alpha-synuclein protein can adopt several different conformations that cause neurodegeneration. Different alpha-synuclein conformers cause at least three distinct alpha-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressingmutant alpha-synuclein (A53T) but not to cells expressing alpha-synuclein (E46K). Now, we report that DLB is caused by a strain of alpha-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant alpha-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of alpha-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant alpha-synuclein protein that is permissive for PD prion replication. Our findings suggest that other alpha-synuclein mutants should give further insights into alpha-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other a-synucleinopathies.