Abstract
Alpha-synuclein is considered the major pathological protein associated with Parkinson’s disease, but there is still no effective immunotherapy which targets alpha-synuclein. In order to create a safer and more effective therapy against PD, we are targeting an epitope of alpha-synuclein rather than full-length alpha-synuclein. We have selected several antigenic domains (B-cell epitope) through antigenicity prediction, and also made several recombinant protein fragments from alpha-synuclein upon antigenicity prediction in an E. coli system. We then tested the function of each of the peptides and recombinant fragments in aggregation, their toxicity and antigenicity. We have discovered that the full-length recombinant (aa1–140) can aggregate into oligomers or even fibrils, and fragment aa15–65 can promote the aggregation of aa1–140. It is worth noting that it not only promotes whole protein aggregation, but also self-aggregates as seen by western blotting and silver staining assays. We have tested all candidates on primary neurons for their toxicity and discovered that aa15–65 is the most toxic domain compared to all other fragments. The antibody targeting this domain also showed both anti-aggregation activity and some therapeutic effect. Therefore, we believe that we have identified the most potent therapeutic domain of alpha synuclein as a therapeutic target.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder [1]
The major breakthroughs in immunotherapy against AD is attributed to the successful identification of pathological proteins like amyloid beta (Aβ) and Tau, using them as targets for a cure [50,51,52,53,54]
Alpha synuclein is more difficult to use as a therapeutic target
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder [1]. The history of PD’s discovery dates back to 1817, and it was first described as a “shaking palsy” by Dr James Parkinson [2]. Lewy bodies (LBs) and Lewy neurites (LNs) were attributed to the aggregated forms of α-synuclein accumulates [3]. SNCA gene mutations, which lead to α-synuclein protein misfolding, were the first demonstrated genetic cause of familial Parkinsonism with Lewy pathology [11]. Under some pathogenic conditions, α-synuclein tends to form oligomers, which have high toxicity and induce cell death [12]. Articles discussing Lewy bodies revealed that the clinical progression of PD correlates with α-synuclein progressively spreading and aggregating [13,14,15]. It is strongly suggested that the spread of aggregated α-synuclein leads to the progression of PD. Stopping the spread of aggregated α-synuclein might be the best approach, or even the solution, for treating PD
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