Suppression of autophagy in the brain of transgenic mice with overexpression of А53Т-mutant α-synuclein as an early event at synucleinopathy progression. (13th April 2018)

• Record Type: Journal Article
• Authors: Pupyshev, Alexander B.; Korolenko, Tatiana A.; Akopyan, Anna A.; Amstislavskaya, Tamara G.; Tikhonova, Maria A.
• Is Part Of: Neuroscience letters. Volume 672(2018)
• Page Start: 140
• Page End: 144
• Publication Date: 2018-04-13
• Subjects: B6.Cg-Tg transgenic mouse strain B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J -- CMA chaperone-mediated autophagy -- 6-OHDA 6-hydroxy dopamine -- LC3-II light chain 3 of the microtubule-associated protein 1 conjugated with phosphatidylethanolamine -- PD Parkinson's disease -- TH tyrosine hydroxylase; Autophagy -- Parkinson's disease -- А53Т-mutant α-synuclein -- Animal model -- Mouse -- LC3-II; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2017.12.001
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Mutant α-synuclein overexpression in mice induces autophagy suppression in the brain. The autophagy suppression is stronger in the striatum than in s.nigra. Autophagy decline in young transgenic mice is an early sign of dopaminergic dysfunction. Abstract: Transgenic overexpression of α-synuclein is a common model of Parkinson's disease (PD). Accumulation of А53Т-mutant α-synuclein induces three autophagy cell responses: the inhibition of autophagy caused by the accumulation of α-synuclein, compensatory activation of macroautophagy in response to inhibition of the chaperone-mediated autophagy, and toxic effects of mutant α-synuclein accompanied by the activation of autophagy. The overall effect of long-term overexpression of mutant α-synuclein in vivo remains unclear. Here we evaluated the activity of autophagy in the frontal cortex, striatum and s.nigra of transgenic mice with overexpression of А53Т-mutant α-synuclein. We revealed low autophagic activity in the dopaminergic structures of 5 mo. transgenic B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J mice as compared to controls C57Bl/6J mice. The results were further supported by the data on tyrosine hydroxylase immunostaining that indicated its significant decrease in the striatum but not in s.nigra of transgenic mice and might be more related to earlier damage of dopaminergic neurites than to the somas due to disturbed formation of autophagosomes at the neuron periphery. The results provide evidence of a possible contribution of suppressed autophagy to the development of PD-like condition as an early event at synucleinopathy progression. Activation of autophagy at early stages of PD seems to be a promising therapeutic tool while B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J mice are suggested as a suitable and adequate model for studying the neuroprotective potential and value of this approach.