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Alpha-synuclein as driving force in Parkinson's disease and multiple system atrophy

Book - Dissertation

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder, affecting about 1% of the population over 60. The increase in life expectancy is estimated to double the prevalence of PD in 20 years, expanding the personal, medical and economic burden. Alpha-synuclein (a-SYN) aggregates are found in the brain of PD patients, but this important hallmark is also present in other neurodegenerative disorders, like multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), termed together as synucleinopathies. MSA has a notably lower prevalence than PD. Nevertheless, more research is necessary since it is a devastating condition which arises in the younger population and develops more aggressively. In this thesis, I focused on a-SYN pathology as the key player in both PD and MSA by investigating different features which influence the progression of phenotypic as well as pathological traits in synucleinopathies. In the first part of this thesis, we focused on the relevance of synaptic activity in PD. Synaptic activity and a-SYN are linked at different levels. In physiological conditions, α-SYN is enriched at the synapse where it is involved in synaptic vesicle release. While in pathological conditions, a-SYN aggregation disturbs normal neuronal functioning by altering the synaptic function. Neuronal modulation, like deep brain stimulation (DBS), is a possible treatment for a selective cohort of PD patients. However, it is unclear how modulation of dopaminergic neurons affects a-SYN pathology. Employing an a-SYN-based rat model for PD, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in order to artificially modulate neuronal activity of the nigral dopaminergic neurons. We observed that chronic neuronal activation results in worsening of motor function, without altering dopaminergic neurodegeneration. Moreover, increased neuronal activity altered the biochemical properties of a-SYN, linking neuronal activity to the pathophysiological role of a-SYN in PD. In the second part, we studied the role of different a-SYN strains in an MSA mouse model. The existence of a-SYN strains might explain the flexibility of a-SYN to induce distinct synucleinopathies. This hypothesis is supported by recent studies which investigated the properties of a-SYN aggregates isolated from the different synucleinopathies patients. We have previously shown that injection of recombinant a-SYN fibrillar strains (fibrils and ribbons) in a PD rat model induced distinct phenotypes and pathological hallmarks. In the present study, we aimed to study the relevance of the cellular environment in the progression of MSA. To do so we used an MSA mouse model, overexpressing a-SYN in oligodendrocytes as opposed to our α-SYN-based PD model where α-SYN was expressed by neurons. Administration of fibrillar a-SYN to the MSA transgenic model aggravates the motor deficits and disease pathological hallmarks, creating a better model for MSA. However, we found that α-SYN fibrils induced a significantly worse phenotype compared to α-SYN ribbons, analogously to what we observed in our previous study applying the PD neuronal model. Modifying the cellular environment in which a-SYN is overexpressed did not change the fact that the α-SYN fibrils are the most toxic in both models. We further show that the immune response generated against the different α-SYN strains is altered depending on the conformation. With this study we show that the resulting disease phenotype in MSA depends on the protein strain, however it is probably influenced by the host environment. Overall, this work investigated several aspects of the pathogenesis of synucleinopathies seeking to shed light on this complex matter. The gradually increasing knowledge of the pathological aspect of a-SYN aggregation as well as the host response, boosts the optimism of finding diagnostic tools and efficient therapeutic approaches to cure this devastating group of diseases.
Publication year:2020
Accessibility:Open