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  • Parkinson pathology propagation and long-distance transport in neurons
    Publication . Domingues, Joana Manuel Portela; Araújo, Inês
    Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting 1% of the population over 55 years of age [5]. Alpha synuclein (α-Syn) aggregation has been closely linked to its aetiology. Pathologically PD is characterized by the progressive loss of nigrostriatal dopaminergic neurons and the presence of protein inclusions predominantly composed of fibrillar α-Syn termed Lewy bodies within dopaminergic neurons. Although current treatments can ameliorate the symptoms of PD, there are no available therapies that would slow-down or stop the progression of the disease. Since 1997, when it was discovered that a missense mutation in the gene for α-Syn caused familial PD, the role of α-Syn in the aetiology and pathology has been extensively studied. Development and characterization of α-Syn-based animal models are crucial steps to understand pathogenesis of the disease, as well as to provide a framework to test therapeutic strategies. Here, and with the main goal of study the Parkinson pathology propagation, we coinjected adeno-associated virus (AAV) vectors encoding α-Syn fused to either the N- or C-terminal of Venus in rat brain areas affected in PD such as motor cortex (CX group), striatum (ST group) or substantia nigra (SN group) and describe a novel viral vector rodent model with the ability to directly detect and track α-Syn aggregation in vivo. For this purpose we used the bimolecular fluorescence complementation (BiFC) assay. Viral coinjection resulted in widespread Venus signal within the corticospinal tract (CX group) and within the nigrostriatal pathway (ST and SN groups) including cell bodies in the injection sites and synaptic accumulation, suggestive of α-Syn oligomers formation. Transduced rats showed axonal swellings. However, there was no significant neuron loss in the substantia nigra of SN group and no significant loss of nerve terminals in the stiatum of SN and ST group. Concordant with this, both groups also did not exhibit any behavioural impairment or signs of neuroinflammation. We have developed an animal model that provides a tool for Parkinson’s disease research allowing the direct detection of α-Syn oligomers in vivo and ultimately, the knowledge coming from it will be essential for the study of this pathology as well as for the development of novel therapeutic strategies for intervention in PD.
    2014Dissertação de mestrado Acesso aberto Ver mais