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α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice

Norihito Uemura1, Nicholas P Marotta2, Jahan Ara2

  • 1Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104-2676, USA. nuemura@kuhp.kyoto-u.ac.jp.

Nature Communications
|October 29, 2023
PubMed

Insights

Amplified Lewy body alpha-Synuclein (αSyn) aggregates accurately model Lewy body disease (LBD) pathology in mice. This new model preserves the unique biological and conformational features of αSyn found in LBD brains.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Extraction of alpha-Synuclein (αSyn) aggregates from Lewy body disease (LBD) brains is established, but replicating their properties via templated fibrillization is challenging.
  • Amplified LB-αSyn (ampLB) exhibits distinct in vitro biological activities compared to de novo human αSyn preformed fibrils (hPFF).

Purpose of the Study:

  • To compare the in vivo biological activities of hPFF and ampLB.
  • To evaluate their efficacy in modeling Lewy body disease (LBD) pathology.

Main Methods:

  • Injection of ampLB and hPFF into mice expressing human αSyn (Thy1:SNCA/Snca-/-).
  • Assessment of seeding activity, pathology latency, distribution, inclusion morphology, and cell-type preference.
  • Analysis of αSyn aggregate features in injected mice.

Main Results:

  • ampLB injection induced LBD-like pathologies distinct from hPFF injection or aging.
  • Pathologies in ampLB-injected mice mimicked those in human LBD subjects.
  • αSyn aggregates in ampLB-injected mice retained original LB-αSyn biological and conformational features.

Conclusions:

  • ampLB injection serves as a faithful model for key aspects of Lewy body disease (LBD).
  • This approach is superior to conventional PFF injection or αSyn overexpression for LBD modeling.

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