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

被引：53

作者：

Ayers, Jacob I. ^{[1
,2
]}

Lee, Joanne ^{[1
]}

Monteiro, Octovia ^{[1
]}

Woerman, Amanda L. ^{[1
,2
]}

Lazar, Ann A. ^{[3
,4
]}

Condello, Carlo ^{[1
,2
]}

Paras, Nick A. ^{[1
,2
]}

Prusiner, Stanley B. ^{[1
,2
,5
]}

机构：

[1] Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Div Biostat, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Div Oral Epidemiol & Dent Publ Hlth, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2022年 / 119卷 / 06期

关键词：

neurodegeneration; dementia with Lewy bodies; synucleinopathies; strains; prions; GLIAL CYTOPLASMIC INCLUSIONS; PARKINSONS-DISEASE; PATHOLOGY; MUTATION; NEURONS;

D O I：

10.1073/pnas.2113489119

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9

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