Parkinson’s disease progression
In PD, a substantial cell loss in the substantia nigra occurs simultaneously with the formation of abnormal protein aggregates inside the nerve cells. Termed Lewy Bodies (LB), these aggregates are composed of mostly synuclein. Recent evidence suggests that α-synuclein may be responsible for initiating and spreading the pathological process in PD. The EU-funded project AGELYSPARK (Role of the lysosomal dysfunction during aging, and implication for Parkinson’s Disease) focused on unravelling this process. The project developed clinically relevant mouse and primate models by studying the interaction of multiple likely causes of cell death in PD. To assess the role of the lysosomal dysfunction during ageing, AGELYSPARK inhibited the lysosomal-mediated degradation pathway in an in vitro model of senescence-accelerated cells. In vivo testing was performed on senescence-accelerated mouse models, characterised by age-dependent aggregates formation. By establishing new models combining ageing and lysosomal impairment, it was possible to study the mechanisms of formation and potential significance of LB-like inclusions. The main hypothesis investigated by AGELYSPARK was whether the presence of a pathogenic factor in the brain could trigger LB aggregate formation. In vivo testing included injecting fractions of cerebrospinal fluid from PD patients in the brains of animal models. In both mice and monkeys, inoculations of PD-derived LB extracts caused progressive neurodegeneration starting at striatal dopaminergic terminals. This indicates that insoluble forms of α-synuclein that are contained in PD-derived LB are indeed pathogenic. These results have important implications for the development of disease-modifying therapies for PD, aimed at targeting expression levels, pathological conversion and/or cell-to-cell transmission of α-synuclein.
Keywords
Parkinson’s disease, animal model, neurodegeneration, Lewy bodies, α-synuclein, autophagy-lysosomal pathway, ATP13A2
