TY - JOUR

T1 - Suppression of autophagy in the brain of transgenic mice with overexpression of А53Т-mutant α-synuclein as an early event at synucleinopathy progression

AU - Pupyshev, Alexander B.

AU - Korolenko, Tatiana A.

AU - Akopyan, Anna A.

AU - Amstislavskaya, Tamara G.

AU - Tikhonova, Maria A.

N1 - Publisher Copyright: © 2017 Elsevier B.V.

PY - 2018/4/13

Y1 - 2018/4/13

N2 - 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.

AB - 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.

KW - Animal model

KW - Autophagy

KW - LC3-II

KW - Mouse

KW - Parkinson's disease

KW - А53Т-mutant α-synuclein

KW - IMPAIRS MACROAUTOPHAGY

KW - MODELS

KW - CHAPERONE-MEDIATED AUTOPHAGY

KW - EXPRESSION

KW - A53T-mutant alpha-synuclein

KW - PARKINSONS-DISEASE

KW - Parkinson Disease/genetics

KW - Autophagy/genetics

KW - alpha-Synuclein/genetics

KW - Substantia Nigra/metabolism

KW - Disease Models, Animal

KW - Tyrosine 3-Monooxygenase/metabolism

KW - Mice, Transgenic

KW - Dopaminergic Neurons/metabolism

KW - Disease Progression

KW - Frontal Lobe/metabolism

KW - Corpus Striatum/metabolism

KW - Animals

KW - Mice

UR - http://www.scopus.com/inward/record.url?scp=85044130225&partnerID=8YFLogxK

U2 - 10.1016/j.neulet.2017.12.001

DO - 10.1016/j.neulet.2017.12.001

M3 - Article

C2 - 29203207

AN - SCOPUS:85044130225

VL - 672

SP - 140

EP - 144

JO - Neuroscience Letters

JF - Neuroscience Letters

SN - 0304-3940

ER -