Editor-in-Chief Hatice Kübra Elçioğlu Vice Editors Levent Kabasakal Esra Tatar Online ISSN 2630-6344 Publisher Marmara University Frequency Bimonthly (Six issues / year) Abbreviation J.Res.Pharm. Former Name Marmara Pharmaceutical Journal
Journal of Research in Pharmacy 2021 , Vol 25 , Issue 3
Higher alpha-synuclein aggregate density does not lead to more severe dopaminergic cell loss in the AAV-mediated overexpression model of Parkinson’s Disease: A time-course study
Banu Cahide TEL1,İnci KAZKAYASI1,Gökçen TELLİ1,Elif ÇINAR2,Sevgi Uğur MUTLUAY1,Gül YALÇIN-ÇAKMAKLI3,Esen SAKA3, Bülent ELİBOL3
1Department of Pharmacology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
2Department of Pharmacology, Faculty of Pharmacy, Zonguldak Bülent Ecevit University, Zonguldak, Turkey
3Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
DOI : 10.29228/jrp.25 Pathological intracellular aggregation of alpha-synuclein (a-syn) is the hallmark of Parkinson’s disease (PD). Our aim is to explore the outcomes of long-term a-syn pathology with its functional correlates in the PD model by AAV (adeno-associated virus)-mediated a-syn overexpression in substantia nigra (SN). Female Wistar rats (220-260 g) received a unilateral injection of AAV-human-a-syn or green fluorescent protein (GFP) gene into the SN. The animals were tested for motor functions with cylinder test at 8, 12 weeks or 9 months post-injection. The intensity of a-syn accumulation or GFP in striatum and dopaminergic neuronal loss in SN, dopaminergic terminal loss in striatum and synaptic integrity were analyzed by a-syn, GFP, tyrosine hydroxylase (TH) and synaptophsin immunohistochemistry, respectively. At all time-points, AAV-human-a-syn injected animals displayed more motor dysfunction and TH-positive cell loss compared to AAV-GFP injected group. A-syn immunoreactivity was present in the nigral neurons as well as the striatal terminals in all animals that received AAV-a-syn. Striatal TH density analysis showed a decrease in both 12-weeks and 9 months a-syn groups compared to controls. However, TH-positive neuron count was lower in 9-months group compared to 12-weeks group. Hence, the motor performance of 9-month group showed an improvement which may be a sign of a compensatory mechanisms against a-syn-induced neurodegeneration. The findings of this study implicate that higher a-syn density in SN does not always lead to worse motor function or more severe dopaminergic cell loss. This may support the hypothesis that a-syn aggregates are the end-product of a cellular defense mechanism rather than being causative pathology. Keywords : Alpha-synuclein; Parkinson’s disease; adeno associated viral vectors; animal model
Marmara University