期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：6
DOI：10.1073/pnas.2113489119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are caused by α-synuclein prions that differ from each other and from those causing Parkinson’s disease (PD). DLB prions differ in their infectivity from those causing MSA or PD. The wild-type, normal version of the α-synuclein protein has the acidic amino acid glutamate (E) at residue 46, while in cases of inherited PD, it is mutated to the basic amino acid lysine (K). Using genetically engineered α-synuclein, we identified unique conditions for propagating MSA and DLB prions. Being able to distinguish among strains of naturally occurring α-synuclein prions may make it possible to develop strain-specific therapeutics for MSA, DLB, and PD.
The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-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 expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-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 α-synucleinopathies.
关键词：enneurodegenerationdementia with Lewy bodiessynucleinopathiesstrainsprions
