Abstract
Alpha synuclein has a key role in the pathogenesis of Parkinson’s disease (PD), Dementia with Lewy Bodies (LBD) and Multiple System Atrophy (MSA). Immunotherapies aiming at neutralising toxic αSyn species are being investigated in the clinic as potential disease modifying therapies for PD and other synucleinopathies. In this study, the effects of active immunisation against αSyn with the UB-312 vaccine were investigated in the Thy1SNCA/15 mouse model of PD. Young transgenic and wild-type mice received an immunisation regimen over a period of 6 weeks, then observed for an additional 9 weeks. Behavioural assessment was conducted before immunisation and at 15 weeks after the first dose. UB-312 immunisation prevented the development of motor impairment in the wire test and challenging beam test, which was associated with reduced levels of αSyn oligomers in the cerebral cortex, hippocampus and striatum of Thy1SNCA/15 mice. UB-312 immunotherapy resulted in a significant reduction of theαSyn load in the colon, accompanied by a reduction in enteric glial cell reactivity in the colonic ganglia. Our results demonstrate that immunisation with UB-312 prevents functional deficits and both central and peripheral pathology in Thy1SNCA/15 mice.
Highlights
Synucleinopathies are chronic progressive neurodegenerative diseases that are characterised by accumulation of alpha-synuclein in the brain
This study aims to investigate whether UB-312 immunotherapy has an effect on gastrointestinal pathology in order to assess its potential in the treatment of prodromal Parkinson's disease (PD) cases that manifest early GI complications
Some Wt and Transgenic mice administered adjuvant produced background antibody titres, but these were 2–3 orders of magnitude lower than UB-312 induced titres. The cause of this is not clear and the detection of antibody titres was 2–3 orders of magnitude lower than UB-312 induced antibody titres. Since this was observed at comparable levels in both the Wt and Thy1SNCA/15 adjuvant treated mice, it is unlikely to be a response of the rodent immune system to the human αSyn transgene
Summary
Synucleinopathies are chronic progressive neurodegenerative diseases that are characterised by accumulation of alpha-synuclein (αSyn) in the brain. A number of studies have demonstrated that extracellular αSyn plays a role in disease and is involved in the propagation of αSyn between neurons. Internalisation of the protein by neighbouring cells results in the formation of protein aggregates, which could result in the propagation of the disease to anatomically connected brain regions [10, 25]. This mechanism has been demonstrated in cell
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