Characterization of the nigrostriatal pathway in Parkinson's Disease mice models of overexpression of human alpha-synuclein and LRRK2 mutants

Abstract

Parkinson's disease (PD) is a long-term neurodegenerative disease with a complex array of symptoms and signs, involving general symptoms such as pain and fatigue, but mostly characterised by loss of motor coordination and late-stage psychological disorders such as psychosis and dementia. Other key signs of PD are loss of dopamine and neuronal death in the nigrostriatal pathway, most notably dopaminergic neurons of the substantia nigra pars compacta, found on the ventrolateral side of the midbrain, leading to loss of dopaminergic input in the caudate and putamen of the basal ganglia (also called striatum); and the appearance of Lewy bodies and Lewy neurites, the previous being alpha-synuclein in the soma of neurons and the latter in cell processes. To date, PD is the second most prevalent neurodegenerative disease after Alzheimer’s disease. It has been reported to have a prevalence of 1-2 people out of 1000 at all times in unselected populations, affecting 1% of people over the age of 60 worldwide. This number of affected people is growing, and certain authors, experts in the topic of PD, estimate that the number of people affected by PD will exceed 12 million worldwide by 2040. Several strategies have been studied to attempt to stop the neurodegenerative process and increase the quality of life of PD patients, yet unfortunately so far no cure or therapy has been found for this disease. It is important to then continue to research PD, and this requires models to assess novel therapeutical approaches. In this thesis, we study two different mice PD models: C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J and C57BL/6J-Tg(LRRK2*G2019S)2AMjff/J, and we use different strategies to improve the models for future preclinical data for therapeutic studies. We were able to find that our C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J mice presented higher content in striatal dopamine, reactive microgliosis in the nigrostriatal pathway and motor dysfunctions with hypoactivity. When challenged with a chronic scheme of MPTP, we are not able to observe any exacerbated damage respect to a treated WT littermate, less responsive microgliosis and astrogliosis. And finally, when aged for 18 months, we also fail to observe any differential effect on these mice. C57BL/6J-Tg(LRRK2*G2019S)2AMjff/J mice exhibited no nigrostriatal damage, weak reactive microgliosis, and no motor problems. When challenged with the chronic scheme of MPTP, no exacerbated nigrostriatal damage was observed, and like the C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J mice, a less responsive microgliosis and astrogliosis than the WT littermate was found. On another note, aging for 18 months does not provoke any increased nigrostriatal degeneration or motor problems. Finally, an analysis of striatal interneurons showed a decrease in parvalbumin fast-spiking neurons and thyrotropin-releasing hormone neurons specific to these models. Another strategy that was followed was to crossbreed these two mice, generating a mouse strain that has an increased striatal dopamine content, as well as reactive microgliosis, but unlike the C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J this strain shows a hyperactive behaviour with motor dysfunction. Striatal interneuron population is also affected with reduced parvalbumin fast-spiking neurons and thyrotropin-releasing hormone neurons. These mice were also aged for 18 months, and no exacerbated nigral damage was observed or any exaggerated motor phenotype.