Modelling Parkinson in zebrafish: from understanding disease to discovering new therapies

Abstract

The term "neurodegenerative disorder" refers to a set of illnesses in which the neurological system gradually deteriorates and is characterized by cognitive impairment, motor degradation, and behavioural changes. The second-most prevalent neurodegenerative condition among them is Parkinson's disease (PD). Environmental and genetic variables combine intricately to cause PD, according to the aetiology. The latter affects 10–20% of patients, and many genes have been identified as a contributing factor. As Parkinson's disease cannot currently be prevented, slowed, or cured, the identification of novel biomarkers is of utmost relevance for the development of successful pharmacological therapy. In order to shed light on the pathogenic underpinnings of this crippling disease, it is crucial to create animal models that mimic the onset, course, and symptomatology of the pathology. This thesis' major goal is to create a set of genetic and pharmacological zebrafish models of Parkinson's disease that may be used to find new therapeutic targets and medications that could be effective in treating the disease. The findings of this thesis project show that the selected genetic models - overexpression of park1/snca and loss-of-function of park2/parkin, park6/pink1, park7/DJ-1, and park8/lrrk2 - exhibit a subset of phenotypes that are consistent with those observed in Parkinson's disease patients, namely defects in locomotion and loss of dopaminergic neurons. Transcriptomic data from neurons isolated from the same genetic models reveal numerous dysregulated genes that have been previously linked to Parkinson's disease or to symptoms related to the disease, such as mitochondrial dysfunction, inflammatory response, or death. Overall, the work done for this thesis project has created a strong in vivo platform that can be used to find new therapeutic targets and, more significantly, to validate those targets and prospective compounds that could be used to modulate their activity.The term "neurodegenerative disorder" refers to a set of illnesses in which the neurological system gradually deteriorates and is characterized by cognitive impairment, motor degradation, and behavioural changes. The second-most prevalent neurodegenerative condition among them is Parkinson's disease (PD). Environmental and genetic variables combine intricately to cause PD, according to the aetiology. The latter affects 10–20% of patients, and many genes have been identified as a contributing factor. As Parkinson's disease cannot currently be prevented, slowed, or cured, the identification of novel biomarkers is of utmost relevance for the development of successful pharmacological therapy. In order to shed light on the pathogenic underpinnings of this crippling disease, it is crucial to create animal models that mimic the onset, course, and symptomatology of the pathology. This thesis' major goal is to create a set of genetic and pharmacological zebrafish models of Parkinson's disease that may be used to find new therapeutic targets and medications that could be effective in treating the disease. The findings of this thesis project show that the selected genetic models - overexpression of park1/snca and loss-of-function of park2/parkin, park6/pink1, park7/DJ-1, and park8/lrrk2 - exhibit a subset of phenotypes that are consistent with those observed in Parkinson's disease patients, namely defects in locomotion and loss of dopaminergic neurons. Transcriptomic data from neurons isolated from the same genetic models reveal numerous dysregulated genes that have been previously linked to Parkinson's disease or to symptoms related to the disease, such as mitochondrial dysfunction, inflammatory response, or death. Overall, the work done for this thesis project has created a strong in vivo platform that can be used to find new therapeutic targets and, more significantly, to validate those targets and prospective compounds that could be used to modulate their activity.Programa de Doctorat en Biomedicina