Parkinson's disease (PD) is a progressive and currently incurable
neurological disorder characterised by the loss of midbrain dopaminergic
neurons and the accumulation of aggregated alpha-synuclein (a-syn).
Oligomeric a-syn is proposed to play a central role in spreading protein
aggregation in the brain with associated cellular toxicity contributing
to a progressive neurological decline. For this reason, a-syn oligomers
have attracted interest as therapeutic targets for neurodegenerative
conditions such as PD and other alpha-synucleinopathies. In addition to
strategies using small molecules, neutralisation of the toxic oligomers
by antibodies represents an attractive and highly specific strategy for
reducing disease progression. Emerging active immunisation approaches
using vaccines are already being trialled to induce such antibodies.
Here we propose a novel vaccine based on the RNA bacteriophage (Qbeta)
virus-like particle conjugated with short peptides of human a-syn. High
titres of antibodies were successfully and safely generated in wild-type
and human a-syn over-expressing (SNCA-OVX) transgenic mice
following vaccination. Antibodies from vaccine candidates targeting the
C-terminal regions of a-syn were able to recognise Lewy bodies, the
hallmark aggregates in human PD brains. Furthermore, antibodies
specifically targeted oligomeric and aggregated a-syn as they exhibited
100 times greater affinity for oligomeric species over monomer a-syn
proteins in solution. In the SNCA-OVX transgenic mice used, vaccination
was, however, unable to confer significant changes to oligomeric a-syn
bioburden. Similarly, there was no discernible effect of vaccine
treatment on behavioural phenotype as compared to control groups. Thus,
antibodies specific for oligomeric a-syn induced by vaccination were
unable to treat symptoms of PD in this particular mouse model.