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PrPSc Oligomerization Appears Dynamic, Quickly Engendering Inherent M1000 Acute Synaptotoxicity
Simote T Foliaki1, Victoria Lewis1, Abu M T Islam1
1Department of Medicine (RMH), The University of Melbourne, Parkville, Australia.
Biophysical Journal
|June 21, 2020
Summary
Prion diseases involve misfolded prion protein (PrPSc) causing neurodegeneration. This study shows that small, rapidly formed PrPSc oligomers are key to acute synaptic toxicity in prion disease models.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Prion diseases are fatal neurodegenerative conditions linked to the misfolding of cellular prion protein (PrPC) into infectious, abnormal conformers (PrPSc).
- PrPSc is responsible for disease transmission and acute synaptic toxicity, but the precise biophysical characteristics inducing this toxicity are not fully understood.
- Previous research suggests that acutely synaptotoxic PrPSc is oligomeric.
Purpose of the Study:
- To investigate the kinetic and biophysical properties of acutely synaptotoxic ex vivo PrPSc.
- To determine the role of PrPSc oligomerization in acute synaptic dysfunction.
- To compare the properties of PrPSc from diseased brains with those from normal brain homogenates.
Main Methods:
- Size exclusion chromatography was used to isolate PrPSc fractions from M1000 prion disease mouse brains and normal brain homogenates (NBH).
- Fractions approximating monomeric PrP (mM1000, mNBH) and preformed oligomeric fractions (oM1000, oNBH) were assessed for acute synaptotoxicity.
- The effect of epigallocatechin gallate (EGCG) on PrPSc oligomerization and toxicity was evaluated.
- Enzymatic digestion was employed to assess the composition of PrP assemblies.
Main Results:
- Monomeric PrPSc (mM1000) fractions exhibited acute synaptotoxicity comparable to preformed oligomers (oM1000), indicating rapid oligomerization.
- Treatment with EGCG mitigated PrPSc oligomerization and abrogated synaptotoxicity, while oM1000 remained toxic.
- Normal brain homogenate monomers (mNBH) and oligomers (oNBH) were not acutely synaptotoxic.
- PrPSc oligomers resisted enzymatic digestion, unlike NBH oligomers which were reduced by nucleic acid digestion.
Conclusions:
- PrPSc oligomerization into small, multimeric assemblies is critical for inducing acute synaptotoxicity.
- Acutely synaptotoxic PrPSc exists in dynamic equilibrium between monomers capable of rapid aggregation and stable, tightly associated small oligomers.
- These findings highlight the importance of PrPSc oligomerization state in the pathogenesis of prion-related synaptic dysfunction.
