Suppression of autophagy in the brain of transgenic mice with overexpression of A53T-mutant α-synuclein as an early event at synucleinopathy progression

Transgenic overexpression of a-synuclein is a common model of Parkinson's disease (PD). Accumulation of A53T-mutant alpha-synuclein induces three autophagy cell responses: the inhibition of autophagy caused by the accumulation of alpha-synuclein, compensatory activation of macroautophagy in response to inhibition of the chaperone-mediated autophagy, and toxic effects of mutant a-synuclein accompanied by the activation of autophagy. The overall effect of long-term overexpression of mutant alpha-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 A53T-mutant alpha-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 C57BI/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 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.