The Effects of Prolyl Oligopeptidase Inhibition in α-Synuclein Based Mouse Models of Parkinson's Disease
Year: 2015
Type: dissertation
Abstract: Parkinson's disease (PD) is characterized by a slow and gradual loss of neurons and subsequent loss of neurotransmitter dopamine in the movement-related nigrostriatal brain tracts. This causes symptoms of PD, which are resting tremor, rigidity and slowness of movement. Genetic and environmental factors are linked to PD, but its etiology is still largely unknown. Current drug therapies can only relieve the symptoms of PD but treatment to stop or delay the disease progression does not exist at the moment. The main findings in neuropathological characterization of the brain regions that are influenced in PD, are abnormal intraneuronal protein inclusions, called Lewy bodies. Insoluble, aggregated α-synuclein (aSyn) protein is the most abundant component of Lewy bodies. Pathological aggregation and accumulation of aSyn is associated with neuronal death in PD. Therefore, approaches to target aSyn as a potential disease-modifying treatment for PD have been under investigation. The aim of this study was to examine the role of prolyl oligopeptidase (PREP) and pharmacological inhibition of its enzymatic activity by KYP-2047 in aSyn aggregation. Using purified proteins and cell culture model, we showed that PREP forms direct protein-protein interaction with aSyn, thus enhancing its aggregation. KYP-2047 reduced the PREP-mediated aSyn aggregation in cell culture. Then the effects of PREP inhibition on aSyn aggregation were examined in vivo. The purpose was to first characterize a genetic mouse model, carrying mouse A30P mutated aSyn, which is linked to early-onset PD in humans, in order to find out if the mutated mouse aSyn is more prone to aggregate; and to cause PD-like phenotype. The effects of KYP-2047 treatments were assessed in the model. The main findings were that the A30P mutation in mouse aSyn protein caused minor hyperactive behaviour but did not change the brain dopamine levels, and A30P aSyn accumulated in the brain more than wildtype aSyn by age. KYP-2047 treatment reduced the amount of A30P aSyn in immunohistochemical analysis, and the reduction was more specific for high-molecular weight aSyn oligomers in Western blot analysis. We also observed increased autophagy markers in brain tissue. Therefore, PREP inhibition was further studied in cell culture, where it was shown to enhance macroautophagic protein clearance pathway, which is an important pathway in the degradation of high-molecular weight aSyn forms. In the last study, the effects of KYP-2047 were examined in a mouse model of PD that was based on lactacystin-induced inhibition of ubiquitin-proteasome protein degradation pathway. Proteasome inhibition was shown to induce rapid PD-like neurodegeneration recapitulating the cardinal features of PD. KYP-2047 treatment partially protected dopaminergic neurons in the brain and had beneficial effect on motor behaviour, but did not have an effect on aSyn amount. Taken together, this study has provided new insights into the role of PREP in aSyn aggregation and suggest that PREP inhibition has beneficial effects on reducing the aggregation process via two mechanisms. PREP inhibition could be promising and further assessed in the treatment of PD, other α-synucleinopathies and possibly other protein accumulation diseases.
Source: Työväentutkimus Vuosikirja
Author: Mari Savolainen
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2192731896