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Behaviour Phenotyping of Parkinson’s Disease Animal Models Using Inertial Sensors
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Resumo(s)
Parkinson’s Disease is a progressive degenerative illness of the human nervous system that affects basal ganglia circuits. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, loss of dopaminergic terminals in the striatum and widespread intracellular α-synuclein accumulation. Parkinson’s disease patients present three main motor symptoms: bradykinesia, muscular rigidity and tremor. Nevertheless, patients can also have additional motor and non-motor symptoms, such as apathy, depression, constipation, sleep behavior disorders, loss of sense of smell and cognitive impairment. At the time patients are first diagnosed, the loss of dopaminergic neurons in the substantia nigra pars compacta is already marked and the neurodegeneration has spread to other central nervous system regions. Nowadays, the most effective therapeutic strategy for Parkinson is the administration of Levodopa, a precursor of dopamine, that restores dopaminergic transmission in the nigrostriatal pathway. Nevertheless, Levodopa does not have an effect on the progression of the disease and its continuous administration induces the appearance of dyskinesias. These factors illustrate the importance of searching for novel ways of assessing these disease manifestations at early stages and why finding biomarkers that can reflect the disease progression would play an important role in clinical trials and in research using animal models, that are essential for the testing of new therapeutic approaches. As mentioned above, one way to study the degenerative process leading to Parkinson is using animal models. The MitoPark mice is an animal model for Parkinson Disease that mimics the progressive degeneration of the dopaminergic system through the knockout of the gene for mitochondrial transcription factor A (Tfam) in dopaminergic neurons using the Cre-loxP system. These mice lacking Tfam develop progressive respiratory chain deficiency followed by cell death. As a consequence of the progressive loss of dopaminergic neurons these mice develop Parkinson’s disease-like motor disabilities with ageing. In this project, we accessed both normal and Levodopa-induced behaviour of MitoPark mice using inertial sensors combined with video recordings. The use of inertial sensors allows the acquisition of high-resolution data, bringing the possibility of detecting behaviour patterns as the dopaminergic loss progresses that can be missed by the traditional simple video-tracking approach. Using these sensors we found a new biomarker to track the disease progression in this model that is based on the frequency domain of acceleration recordings. In addition to it, although the MitoPark mice responded to Levodopa with an increase in their acceleration and speed, the Levodopa treatment was not able to decrease the frequency domain of acceleration to control-like values. Altogether, our work shows that motion sensors are adequate for tracking disease progression and allow the measure of novel biomarkers, which may lead to a step further in the current endeavour of searching for novel therapeutic strategies for PD.
Descrição
Tese de mestrado Bioquímica (Bioquímica Médica) Universidade de Lisboa, Faculdade de Ciências, 2021
Palavras-chave
Doença de Parkinson Dopamina MitoPark Sensores de Inércia Levodopa Teses de mestrado - 2021