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Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
Modulation effect of filamentous phage on alpha-synuclein aggregation
Hemi Dimant1, Noa Sharon, Beka Solomon
1Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv 69978, Israel.
Abstract:
Conversion of soluble peptides and proteins into amyloid fibrils and/or intermediate oligomers is believed to be the central event in the pathogenesis of most human neurodegenerative diseases, including Parkinson's disease (PD). Here we describe the modulating effect of filamentous phages on aggregation of alpha-synuclein (AS) in vitro and in a PD cellular model. Filamentous phages, well understood at both structural and genetic levels, have a nanotubular appearance, showing conformational similarities to amyloid fibrils. Since filamentous phages can infect only bacteria and have no tropism to mammalian cells, we utilized the f88 system to present a peptide containing a cyclic RGD (arg-gly-asp), which enabled phage internalization into the cells. Detection of intracellular AS oligomers, in differentiated SH-SY5Y cells, stably transfected with wild type AS gene, was performed using Western blot and ELISA measurements. Data presented here show reduced levels of AS soluble aggregates in phage treated cells compared to non-treated cells, suggesting new therapeutics for PD.
Insights
Filamentous phages reduced alpha-synuclein aggregation in a Parkinson's disease model. This suggests phages could be a novel therapeutic strategy for neurodegenerative diseases like Parkinson's disease.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Amyloid fibril formation from soluble proteins like alpha-synuclein is central to neurodegenerative diseases, including Parkinson's disease (PD).
- Filamentous phages share structural similarities with amyloid fibrils and are well-characterized at genetic and structural levels.
Purpose of the Study:
- To investigate the effect of filamentous phages on alpha-synuclein (AS) aggregation in vitro and in a cellular model of Parkinson's disease.
- To explore the potential of phage-mediated delivery for therapeutic intervention in Parkinson's disease.
Main Methods:
- Utilized the f88 phage display system to present a cyclic RGD peptide for cellular internalization.
- Introduced phages into differentiated SH-SY5Y cells stably transfected with the wild-type alpha-synuclein gene.
- Quantified intracellular AS oligomers using Western blot and ELISA.
Main Results:
- Phage treatment led to reduced levels of soluble alpha-synuclein aggregates in treated cells compared to controls.
- Demonstrated successful internalization of engineered phages into mammalian neuronal cells.
- Confirmed the conformational similarity between filamentous phages and amyloid fibrils.
Conclusions:
- Filamentous phages can modulate alpha-synuclein aggregation, offering a potential new therapeutic avenue for Parkinson's disease.
- Phage-based strategies show promise for targeting intracellular protein aggregation in neurodegenerative diseases.
- Further research into phage therapy for neurodegenerative conditions is warranted.
