Cellular Milieu Imparts Distinct Pathological α-Synuclein Strains in α-Synucleinopathies

Authors

Ronald Gathagan, Thomas Jefferson UniversityFollow
Chao Peng, University of Pennsylvania
Dustin Covell, University of Pennsylvania
Coraima Medellin, University of Pennsylvania
Anna Stieber, University of Pennsylvania
John L. Robinson, University of Pennsylvania
Bin Zhang, University of Pennsylvania
Rose M. Pitkin, University of Pennsylvania
Modupe F. Olufemi, University of Pennsylvania
Kelvin C. Luk, University of Pennsylvania
John Q. Trojanowski, University of Pennsylvania
Virginia M.Y. Lee, University of Pennsylvania

Document Type

Abstract

Publication Date

2-2019

Academic Year

2018-2019

Comments

Poster attached as supplemental file below.

Abstract

Introduction: In Lewy body diseases-including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology -α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites. By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs)

Objective: Our objective was to determine the conformational and biological profiles of a-Syn strains.

Methods: The following methods were used to collect and analyze data: Recombinant α-Syn purification and in vitro fibrillization. Preparation of sarkosyl-insoluble fractions from disease and control brains. Sandwich ELISA. Cell cultures. Stereotaxic injection of sarkosyl-insoluble fraction of pathological α-Syn and α-Syn PFFs. Immunohistochemistry. Purification and depletion of α-Syn from the sarkosyl-insoluble fraction by immunoprecipitation.

Results: GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.

Discussion: Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB- α-Syn, respectively) is conformationally and biologically distinct. Furthermore, we showed that distinct α-Syn strains had no cell type preference in seeding a-Syn pathology and are generated by different intracellular milieus

Recommended Citation

Gathagan, Ronald J.; Peng, Chao; Covell, Dustin J.; Medellin, Coraima; Stieber, Anna; Robinson, John L.; Zhang, Bin; Pitkin, Rose M.; Olufemi, Modupe F.; Luk, Kelvin C.; Trojanowski, John Q.; and Lee, Virginia M.Y., "Cellular Milieu Imparts Distinct Pathological α-Synuclein Strains in α-Synucleinopathies" (2019). SKMC JeffMD Scholarly Inquiry, Phase 1, Project 1.

Language

English