Early Parkinson’s Disease-Like Pathology in a Transgenic Mouse Model Involves a Decreased Cst3 mRNA Expression But Not Neuroinflammatory Response in the Brain

T.A. Korolenko 1 , A.B. Shintyapina 3 , V.M. Belichenko 1 , A.B. Pupyshev 1 , A.A. Akopyan 1 , L.A. Fedoseeva 1 , 4 , G.S. Russkikh 5 , V.A. Vavilin 3 , M.V. Tenditnik 1 , C.-L. Lin 6 , T.G. Amstislavskaya 2 ,  and M.A. Tikhonova 1
  • 1 Laboratory of Experimental Models of Neurodegenerative Processes, Department of Experimental Neuroscience, Scientific Research Institute of Physiology and Basic Medicine, Russia, Novosibirsk
  • 2 Laboratory of Translational Biopsychiatry, Department of Experimental Neuroscience, Scientific Research Institute of Physiology and Basic Medicine, Russia, Novosibirsk
  • 3 Laboratory of Drug Metabolism and Pharmacokinetics, Scientific Research Institute of Molecular Biology and Biophysics, Federal Research Center for Basic and Translational Medicine, Russia, Novosibirsk
  • 4 Laboratory of Evolutionary Genetics, Federal Research Center “Institute of Cytology and Genetics”, Siberian Branch of the Russian Academy of Sciences, Russia, Novosibirsk
  • 5 Scientific Research Institute of Biochemistry, Federal Research Center for Basic and Translational Medicine, , Russia, Novosibirsk
  • 6 Institute of Medicine, Chung Shan Medical University, Taichung

Abstract

Pathological aggregation and accumulation of α-synuclein in neurons play a core role in Parkinson’s disease (PD) while its overexpression is a common PD model. Autophagy-lysosomal pathways are general intraneural mechanisms of protein clearance. Earlier a suppressed autophagy in the brain of young transgenic mice overexpressing the А53Т-mutant human α-synuclein (mut(PD)) was revealed. Previous studies have recognized that Cystatin C displays protective activity against neurodegeneration. This cysteine protease inhibitor attracts particular attention as a potential target for PD treatment related to autophagy modulation. Here we evaluated the mRNA levels of Cst3 encoding Cystatin C in different brain structures of 5 m.o. mut(PD) mice at standard conditions and after the chronic treatment with a neuroprotective agent, ceftriaxone (100 mg/kg, 36 days). The inflammatory markers, namely, microglial activation by IBA1 expression and mRNA levels of two chitinases genes (Chit1, Chia1), were also assessed but no significant difference was found between control and transgenic mice. Cst3 mRNA levels were significantly reduced in the striatum and amygdala in the transgenic PD model. Furthermore, this was associated with autophagy decline and might be added to early signs of synucleinopathy development. We first demonstrated the modulation of mRNA levels of Cst3 and autophagy marker Becn1 in the brain by ceftriaxone treatment. Taken together, the results support the potential of autophagy modulation through Cystatin C at early stages of PD-like pathology.

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