| Zdroj: |
Glud, A N, Lillethorup, T P, Landeck, N, Alstrup, A K O, Johnsen, E L, Brooks, D, Kirik, D, Bjarkam, C, Landau, A M & Sørensen, J C H 2016, ' PROTEIN AGREGATION MODELS OF PARKINSONS DISEASE USING VIRAL VECTORS, PROTEASOME INHIBITION AND INOCULATION OF PREFORMED FIBRILS IN THE GOTTINGEN MINIPIG CNS ', Aarhus University Graduate School of Health, PhD Day 2016: set science free, Danmark, 22/01/2016 . |
| Popis: |
Background:Development of translational models for understanding and treating Parkinson’s disease (PD) are important steps towards clinical applications.The Göttingen minipig (GM) fits progressional neurological models due to a relatively low adult-weight between 20-40 kg, and a large gyrencephalic brain (6x5x4 cm) that can be examined at sufficient resolution using conventional clinical scanning modalities and neuromodulation including preclinical testing of deep brain stimulation and induced pluripotent stem cell (iPSC) grafting.Aim:Using inoculation of human or pig alpha-synuclein (aSYN) fibrils, overexpressing aSYN using Lentivirus (LV) and Adeno Assosiated Virus (AAV) vectors or proteasome inhibition in the nigrostriatal system, we hope to create a new porcine models for PD.Methods:Using conventional human-intended stereotaxic neurosurgery methods, we apply aSYN or preformed fibrils in the catecholamine nigrostriatal system of the GM.The changes are quantified by neurological tests (behavior, scoring and gait), preclinical PET, post mortem analysis of histology and autoradiography.Results:Results from LV methods show "proof of concept" on gait, surgery and histology. AAV models show decrease in activity and velocity over time. PET-imaging of the dopamine system displayed decrease in both AAV and proteasome inhibition models. Discussion:We predict that these models will be beneficial in understanding the pathological mechanisms of human PD, novel therapeutic strategies such as antiaggregant treatment, iPSC, immunotherapy and development of novel radioligands for early diagnosis and assessment of disease progression |
